Formulations of a somatostatin modulator

ABSTRACT

Described herein are formulations of a somatostatin modulator, methods of making such formulations, and methods of using such formulations in the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Patent ApplicationNo. 63/076,024, filed on Sep. 9, 2020, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

Described herein are pharmaceutical compositions and medicamentscomprising a somatostatin modulator, methods of making suchpharmaceutical compositions and medicaments and methods of using suchpharmaceutical compositions and medicaments in the treatment ofconditions, diseases, or disorders that would benefit from modulatingsomatostatin activity.

BACKGROUND OF THE INVENTION

Somatostatin is a peptide hormone that regulates the endocrine systemand affects neurotransmission and cell proliferation via interactionwith G-protein-coupled somatostatin receptors and inhibition of therelease of numerous secondary hormones. Six subtype somatostatinreceptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3,SSTR4, SSTR5) and are encoded by five different somatostatin receptorgenes. Modulation of a particular subtype somatostatin receptor, orcombination thereof, is attractive for the treatment of conditions,diseases, or disorders that would benefit from modulating somatostatinactivity.

SUMMARY OF THE INVENTION

In one aspect, provided herein is a spray-dried solid dispersioncomprising: (a)3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof; and (b) apharmaceutically acceptable polymer; wherein3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof, is dispersedin a polymer matrix formed from the pharmaceutically acceptable polymer.In some embodiments, the pharmaceutically acceptable polymer has a highglass transition temperature (Tg). In some embodiments, thepharmaceutically acceptable polymer comprises polymers of: celluloseoptionally functionalized with any combination of alkyl ethers, alkylesters, phthalate esters; vinyl alcohol; vinyl acetate; propyleneglycol; pyrrolidone; vinylpyrrolidone, oxyethylene; oxypropylene;methacrylic acid; methyl methacrylate; ethylene glycol; ethylene glycolglycerides; ethylene oxide; propylene oxide; 2-ethyl-2-oxazoline; maleicacid; methyl vinyl ether; vinyl caprolactam; or combinations thereof.

In some embodiments, the pharmaceutically acceptable polymer ishydroxypropyl methylcellulose (HPMC), hydroxypropyl methyl celluloseacetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl celluloseacetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinylacetate copolymers, polyethylene glycol, polyethylene glycolpolypropylene glycol copolymers, polyvinylpyrrolidone (PVP),polyvinylpyrrolidone polyvinyl acetate copolymers (PVP/VA), polyethylenepolyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene blockcopolymers, cellulose acetate phthalate (CAP), hydroxypropylmethyl-cellulose phthalate (HPMCP), co-polymer of methacrylic acid andmethyl methacrylate, polyethylene glycol glycerides composed of mono-,di- and triglycerides and mono- and diesters of polyethylene glycol,hydroxypropylcellulose, copolymers of ethylene oxide and propylene oxideblocks, poly(2-ethyl-2-oxazoline), poly(maleic acid/methyl vinyl ether),polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graftcopolymer, ethylene oxide/propylene oxide tetra functional blockcopolymer, d-alpha tocopheryl polyethylene glycol 1000 succinate, orcombinations thereof. In some embodiments, the pharmaceuticallyacceptable polymer is hydroxypropyl methyl cellulose acetate succinate(HPMCAS), or polyvinylpyrrolidone polyvinyl acetate copolymers (PVP/VA).In some embodiments, the pharmaceutically acceptable polymer ishydroxypropyl methyl cellulose acetate succinate grade M (HPMCAS-M). Insome embodiments, the pharmaceutically acceptable polymer ispolyvinylpyrrolidone polyvinyl acetate copolymers in a 6:4 ratio (PVP/VA64).

In some embodiments, the weight ratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof, to thepharmaceutically acceptable polymer is from about 1:10 to about 10:1. Insome embodiments, the weight ratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof, to thepharmaceutically acceptable polymer is from about 1:1 to about 1:10. Insome embodiments, the weight ratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof, to thepharmaceutically acceptable polymer is from about 1:4 to about 1:6. Insome embodiments, the weight ratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof, to thepharmaceutically acceptable polymer is from about 1:1.5 to about 1:6.

In some embodiments, the spray-dried solid dispersion comprises at leastabout 5% by weight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the spray-dried solid dispersion comprises at least about10% by weight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the spray-dried solid dispersion comprises about 15% byweight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the spray-dried solid dispersion further comprisesa non-aqueous solvent. In some embodiments, the non-aqueous solvent isselected from the group consisting of tert-butanol, n-propanol,n-butanol, isopropanol, ethanol, methanol, acetone, ethyl acetate,acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, methylacetate, and mixtures thereof. In some embodiments, the non-aqueoussolvent is selected from the group consisting of methanol, acetone, andmixtures thereof. In some embodiments, the non-aqueous solvent ismethanol.

In some embodiments,3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof, issubstantially amorphous.

In some embodiments,3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof, is3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof.

In another aspect, provided herein is a tablet comprising: thespray-dried solid dispersion described herein; one or morepharmaceutical acceptable ingredients selected from the group consistingof one or more diluents, one or more disintegrants, one or morelubricants, one or more glidants; and optionally one or more filmcoating agents.

In another aspect, provided herein is a tablet comprising:3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer; one or morepharmaceutical acceptable ingredients selected from the group consistingof one or more diluents, one or more disintegrants, one or morelubricants, one or more glidants; and optionally one or more filmcoating agents. In some embodiments,3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer is a spray-dried soliddispersion described herein. In some embodiments, the one or morepharmaceutical acceptable ingredients comprise microcrystallinecellulose, mannitol, crospovidone, colloidal silicon dioxide, andmagnesium stearate. In some embodiments, the one or more pharmaceuticalacceptable ingredients comprise microcrystalline cellulose, mannitol,pregelatinized starch croscarmellose sodium crospovidone, sodiumchloride, 1:1 sodium chloride:potassium chloride, colloidal silicondioxide, and magnesium stearate.

In some embodiments, the tablet comprises about 2% by weight to about20% by weight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof. In some embodiments, the tabletcomprises about 2% by weight to about 15% by weight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof. In some embodiments, the tabletcomprises about 2% by weight, about 3% by weight, about 4% by weight,about 5% by weight, about 6% by weight, about 7% by weight, about 8% byweight, about 9% by weight, about 10% by weight, about 11% by weight,about 12% by weight, about 13% by weight, about 14% by weight, or about15% by weight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof. In some embodiments, the tabletcomprises about 10% by weight to about 30% by weight of the polymermatrix formed from the pharmaceutically acceptable polymer. In someembodiments, the tablet comprises about 20% by weight to about 35% byweight of the polymer matrix formed from the pharmaceutically acceptablepolymer.

In some embodiments, the tablet comprises about 2% by weight to about10% by weight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in about 10% by weightto about 30% by weight of a polymer matrix formed from apharmaceutically acceptable polymer; about 40% by weight to about 80% byweight of one or more pharmaceutical acceptable ingredients selectedfrom the group consisting of one or more diluents, one or moredisintegrants, one or more lubricants, one or more glidants; andoptionally less than about 5% by weight of one or more film coatingagents.

In some embodiments, the tablet comprises: about 2% by weight to about10% by weight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in about 10% by weightto about 35% by weight of a polymer matrix formed from apharmaceutically acceptable polymer; about 40% by weight to about 80% byweight of one or more pharmaceutical acceptable ingredients selectedfrom the group consisting of one or more diluents, one or moredisintegrants, one or more lubricants, one or more glidants; andoptionally less than about 5% by weight of one or more film coatingagents.

In some embodiments, the tablet comprises: about 20% by weight to about40% of a spray dried dispersion of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer; about 60% by weightto about 80% by weight of one or more pharmaceutical acceptableingredients selected from the group consisting of one or more diluents,one or more disintegrants, one or more disintegrant aids, one or morelubricants, one or more glidants; and optionally less than about 5% byweight of one or more film coating agents.

In some embodiments, the spray dried dispersion comprises an about 15/85to about 35/65 ratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof to a polymer matrix ofhydroxypropyl methyl cellulose acetate succinate (HPMCAS), orpolyvinylpyrrolidone polyvinyl acetate copolymers (PVP/VA).

In some embodiments, the tablet comprises: about 20% by weight to about35% of a spray dried dispersion of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer; wherein the spraydried dispersion comprises an about 15/85 to about 35/65 ratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof to a polymer matrix ofhydroxypropyl methyl cellulose acetate succinate (HPMCAS), orpolyvinylpyrrolidone polyvinyl acetate copolymers (PVP/VA); about 60% byweight to about 80% by weight of one or more pharmaceutical acceptableingredients selected from the group consisting of microcrystallinecellulose, mannitol, pregelatinized starch, croscarmellose sodium,crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride,silicon dioxide, and magnesium stearate; optionally less than about 5%by weight of one or more film coating agents.

In some embodiments, the tablet comprises: about 20%, about 21%, about22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%,about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, orabout 35% by weight of a spray dried dispersion of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer; wherein the spraydried dispersion comprises an about 15/85 or about 35/65 ratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof to a polymer matrix ofhydroxypropyl methyl cellulose acetate succinate (HPMCAS), orpolyvinylpyrrolidone polyvinyl acetate copolymers (PVP/VA); about 60% byweight to about 80% by weight of one or more pharmaceutical acceptableingredients selected from the group consisting of one or more diluents,one or more disintegrants, one or more disintegrant aids, one or morelubricants, one or more glidants; and optionally less than about 5% byweight of one or more film coating agents.

In some embodiments, the tablet comprises: about 20%, about 21%, about22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%,about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, orabout 35% by weight of a spray dried dispersion of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer; wherein the spraydried dispersion comprises an about 15/85 or about 35/65 ratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof to a polymer matrix ofhydroxypropyl methyl cellulose acetate succinate (HPMCAS), orpolyvinylpyrrolidone polyvinyl acetate copolymers (PVP/VA); about 60% byweight to about 80% by weight of one or more pharmaceutical acceptableingredients selected from the group consisting of microcrystallinecellulose, mannitol, pregelatinized starch, croscarmellose sodium,crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride,silicon dioxide, and magnesium stearate; optionally less than about 5%by weight of one or more film coating agents.

In some embodiments, the tablet comprises about 5 mg, about 10 mg, about20 mg, about 40 mg, about 60 mg or about 80 mg of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof. In some embodiments, the tabletcomprises about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50mg, about 60 mg, about 70 mg, or about 80 mg of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof.

In some embodiments, the tablet comprises about 10 mg of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof. In some embodiments, the tabletcomprises about 20 mg of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof. In some embodiments, the tabletcomprises about 30 mg of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof. In some embodiments, the tabletcomprises about 40 mg of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof. In some embodiments, the tabletcomprises about 50 mg of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof. In some embodiments, the tabletcomprises about 60 mg of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof.

In one aspect, described herein is a method of treating acromegaly orneuroendocrine tumors, or both, in a human comprising orallyadministering to the human with acromegaly or neuroendocrine tumors anyone of the spray-dried dispersion tablets described herein.

In some embodiments, the tablet is administered once daily. In someembodiments, the tablet is administered at least 30 minutes before ameal. In some embodiments, the tablet is administered at least 60minutes before a meal. In some embodiments, the tablet is administeredwith a glass of water on an empty stomach at least 30 minutes before ameal. In some embodiments, the bioavailability of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, from the tablet is notsubstantially affected by the coadministration of proton pumpinhibitors, histamine H2-receptor antagonists, or antacids.

Other features and advantages of the compositions, compounds, andmethods described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Illustrates the observed dose proportionality in humansadministered the HMG capsule formulation or the SDD tablet formulationof Compound A-HCl.

FIG. 2. Illustrates the performance of the HMG capsule formulation andthe SDD tablet formulation of Compound A-HCl in dogs with or withoutpentagastrin pretreatment.

DETAILED DESCRIPTION OF THE INVENTION

Somatostatin (SST), also known as somatotropin release inhibiting factor(SRIF) was initially isolated as a 14-amino acid peptide from ovinehypothalamii (Brazeau et al., Science 179, 77-79, 1973). An N-terminalextended 28-amino acid peptide with similar biological activity to14-amino acid somatostatin was subsequently isolated (Pradayrol et, al.,FEBS Letters, 109, 55-58, 1980; Esch et al., Proc. Natl. Acad. Sci. USA,77, 6827-6831, 1980). SST is a regulatory peptide produced by severalcell types in response to other neuropeptides, neurotransmitters,hormones, cytokines, and growth factors. SST acts through both endocrineand paracrine pathways to affect its target cells. Many of these effectsare related to the inhibition of secretion of other hormones, mostnotably growth hormone (GH). They are produced by a wide variety of celltypes in the central nervous system (CNS) and gut, and have multiplefunctions including modulation of secretion of growth hormone (GH),insulin, glucagon, as well as many other hormones that areanti-proliferative.

These pleotropic actions of somatostatins are mediated by sixsomatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4,SSTR5). The six somatostatin receptor proteins are encoded by fivedifferent somatostatin receptor genes (Reisine and Bell, Endocr Rev. 16,427-442, 1995; Patel and Srikant, Trends Endocrinol Metab 8, 398-405,1997). All the receptors are members of the class-A subgroup of the Gprotein-coupled receptor (GPCR) superfamily. SST2A receptor is the mostwidely expressed subtype in human tumors and is the dominant receptor bywhich GH secretion is suppressed. Unless otherwise stated, the termSSTR2 means SSTR2a.

It is possible to selectively modulate any one of the somatostatinreceptor subtypes, or combination thereof. In some embodiments,selectively modulating any one of the somatostatin receptor subtypesrelative to the other somatostatin receptor subtypes, or combinationthereof, is useful in a variety of clinical applications. In someembodiments, selectively modulating any one of the somatostatin receptorsubtypes relative to the other somatostatin receptor subtypes reducesunwanted side effects in a variety of clinical applications.

For example, modulation of SSTR2 activity mediates the inhibition ofgrowth hormone (GH) release from the anterior pituitary and glucagonrelease from pancreas. SSTR2 is also implicated in many other biologicalfunctions such as, but not limited to, cell proliferation, nociception,inflammation, and angiogenesis. In some embodiments, a selective SSTR2modulator is used in the treatment of acromegaly, gut neuroendocrinetumors, pain, neuropathies, nephropathies, and inflammation, as well asretinopathies resulting from aberrant blood vessel growth. In some otherembodiments, a selective SSTR2 modulator is used in the treatment ofarthritis, pain, cancer, inflammatory bowel disease, irritable bowelsyndrome, Crohn's disease, Cushing's disease, acute lung injury, acuterespiratory distress syndrome, and ophthalmic disorders such asage-related macular degeneration (AMD), diabetic retinopathy, diabeticmacular edema, and Graves ophthalmology, among others.

In some embodiments, SSTR3 agonists inhibit insulin secretion. In someembodiments, SSTR4 agonists exhibit anti-inflammatory andanti-nociceptive effects. In some embodiments, SSTR5 agonists inhibitinsulin secretion. In addition, SSTR5 has also been implicated tomodulate the release of growth hormone.

Somatostatin peptide and its receptor subtypes are also widely expressedin the brain and disruption or diminishment of their activity ispotentially involved in several psychiatric and neurodegenerativediseases. For example, concentrations of somatostatin in the cebrebralcortex and hippocampus are reduced in schizophrenics and one of the mostconsistent neuropathologic findings in this patient group is a deficitin cortical inhibitory interneurons expressing somatostatin.Somatostatin is also highly expressed in brain regions associated withseizures and has also been implicated as having an important role inepilepsy. Somatostatin levels are diminished in the hippocampi ofAlzheimer's and Parkinson's patients, suggesting that restoration of itssignaling as a potential drug target for neurodegeneration.

In one aspect, the compound3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, is a selective nonpeptide SST2biased agonist that is amenable to oral administration to a mammal inneed of treatment with a somatostatin modulator.

In some embodiments, the somatostatin receptor modulator describedherein has utility over a wide range of therapeutic applications. Insome embodiments, the somatostatin receptor modulator described hereinis used in the treatment of a variety of diseases or conditions such as,but not limited to acromegaly, neuroendocrine tumors, retinopathies andother ophthalmic disorders, neuropathy, nephropathy, respiratorydiseases, cancers, pain, neurodegenerative diseases, inflammatorydiseases, as well as psychiatric and neurodegenerative disorders. Insome embodiments, the somatostatin receptor modulator described hereinis used in the treatment of acromegaly, neuroendocrine tumors, or bothin a mammal. In some embodiments, the somatostatin receptor modulatordescribed herein is used in the treatment of acromegaly in a mammal. Insome embodiments, the somatostatin receptor modulator described hereinis used in the treatment of neuroendocrine tumors.

In some embodiments, the somatostatin receptor modulator describedherein inhibits the secretion of various hormones and trophic factors inmammals. In some embodiments, the somatostatin receptor modulatordescribed herein is used to suppress certain endocrine secretions, suchas, but not limited to GH, insulin, glucagon and prolactin. Thesuppression of certain endocrine secretions is useful in the treatmentof disorders such as acromegaly; endocrine tumors such as carcinoids,VIPomas, insulinomas and glucagonomas; or diabetes and diabetes-relatedpathologies, including retinopathy, neuropathy and nephropathy. In someembodiments, the somatostatin receptor modulator described herein isused to suppress exocrine secretions in the pancreas, stomach andintestines, for the treatment of disorders such as pancreatitis,fistulas, bleeding ulcers and diarrhea associated with such diseases asAIDS or cholera. Disorders involving autocrine or paracrine secretionsof trophic factors such as IGF-1 (as well as some endocrine factors)which may be treated by administration of the compounds described hereininclude cancers of the breast, prostate, and lung (both small cell andnon-small cell epidermoids), as well as hepatomas, neuroblastomas, colonand pancreatic adenocarcinomas (ductal type), chondrosarcomas, andmelanomas, diabetic retinopathy, and atherosclerosis associated withvascular grafts and restenosis following angioplasty.

In some embodiments, the somatostatin receptor modulator describedherein is used to suppress the mediators of neurogenic inflammation(e.g. substance P or the tachykinins), and may be used in the treatmentof rheumatoid arthritis; psoriasis; topical inflammation such as isassociated with sunburn, eczema, or other sources of itching;inflammatory bowel disease; irritable bowel syndrome; allergies,including asthma and other respiratory diseases In some otherembodiments, the somatostatin receptor modulators described hereinfunction as neuromodulators in the central nervous system and are usefulin the treatment of Alzheimer's disease and other forms of dementia,pain, and headaches. In some embodiments, the somatostatin receptormodulator described herein provides cytoprotection in disordersinvolving the splanchnic blood flow, including cirrhosis and oesophagalvarices.

Compound A is a somatostatin modulator that is useful in the methods oftreatment described herein.

Compound A

As used herein, Compound A refers to3-(4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl)-2-hydroxy-benzonitrile,which has the chemical structure shown below.

Compound A is a selective nonpeptide SST2 biased agonist. In clinicalstudies, Compound A was shown to have an estimated bioavailability ofabout 70% and an observed half life of about 42 to about 50 hours. Insome embodiments, Compound A is used to treat acromegaly, neuroendocrinetumors, or both. In some embodiments, Compound A is used to treatacromegaly. In some embodiments, Compound A is used to treatneuroendocrine tumors.

In some embodiments, the free base form of Compound A is incorporatedinto the formulations described herein. In some embodiments, Compound Ais incorporated into the formulations described herein as apharmaceutically acceptable salt. In some embodiments, Compound A isincorporated into the formulations described herein as apharmaceutically acceptable solvate.

“Pharmaceutically acceptable,” as used herein, refers a material, suchas a carrier or diluent, which does not abrogate the biological activityor properties of the compound, and is relatively nontoxic, i.e., thematerial is administered to an individual without causing undesirablebiological effects or interacting in a deleterious manner with any ofthe components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a form of atherapeutically active agent that consists of a cationic form of thetherapeutically active agent in combination with a suitable anion, or inalternative embodiments, an anionic form of the therapeutically activeagent in combination with a suitable cation. Handbook of PharmaceuticalSalts: Properties, Selection and Use. International Union of Pure andApplied Chemistry, Wiley-VCH 2002. S. M. Berge, L. D. Bighley, D. C.Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth,editors, Handbook of Pharmaceutical Salts: Properties, Selection andUse, Weinheim/Zürich:Wiley-VCH/VHCA, 2002. Pharmaceutical saltstypically are more soluble and more rapidly soluble in stomach andintestinal juices than non-ionic species and so are useful in soliddosage forms. Furthermore, because their solubility often is a functionof pH, selective dissolution in one or another part of the digestivetract is possible and this capability can be manipulated as one aspectof delayed and sustained release behaviours. Also, because thesalt-forming molecule can be in equilibrium with a neutral form, passagethrough biological membranes can be adjusted.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound disclosed herein with an acid. In some embodiments,the compound disclosed herein (i.e. free base form) is basic and isreacted with an organic acid or an inorganic acid. Inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.Organic acids include, but are not limited to, 1-hydroxy-2-naphthoicacid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid;2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid;acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);benzenesulfonic acid; benzoic acid; camphoric acid (+);camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid(hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamicacid; citric acid; cyclamic acid; dodecylsulfuric acid;ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaricacid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconicacid (D); glucuronic acid (D); glutamic acid; glutaric acid;glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid;lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid(−L); malonic acid; mandelic acid (DL); methanesulfonic acid;naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinicacid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoricacid; proprionic acid; pyroglutamic acid (−L); salicylic acid; sebacicacid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L);thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

In some embodiments, Compound A is incorporated into the formulationsdescribed herein as a pharmaceutically acceptable salt form that isselected from Compound A hydrochloride and Compound A methanesulfonicacid. In some embodiments, the Compound A salt form is Compound Amonohydrochloride. In some embodiments, the Compound A salt form isCompound A dihydrochloride. In some embodiments, the Compound A saltform is Compound A monomethanesulfonic acid. In some embodiments, theCompound A salt form is Compound A dimethanesulfonic acid.

In one aspect, Compound A monohydrochloride (Compound A-HCl) isincorporated into the pharmaceutical compositions described herein.Compound A monohydrochloride (Compound A-HCl), also known as3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, has the following structure:

In some embodiments, the Compound A salt form is amorphous. In someembodiments, Compound A monohydrochloride is amorphous

In some embodiments, the Compound A salt form is crystalline. In someembodiments, Compound A monohydrochloride is crystalline.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms. In someembodiments, solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and are formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, and the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of compounds described herein are conveniently prepared orformed during the processes described herein. In addition, the compoundsprovided herein optionally exist in unsolvated as well as solvatedforms.

Therapeutic agents that are administrable to mammals, such as humans,must be prepared by following regulatory guidelines. Such governmentregulated guidelines are referred to as Good Manufacturing Practice(GMP). GMP guidelines outline acceptable contamination levels of activetherapeutic agents, such as, for example, the amount of residual solventin the final product. Preferred solvents are those that are suitable foruse in GMP facilities and consistent with industrial safety concerns.Categories of solvents are defined in, for example, the InternationalConference on Harmonization of Technical Requirements for Registrationof Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines forResidual Solvents, Q3C(R3), (November 2005).

Solvents are categorized into three classes. Class 1 solvents are toxicand are to be avoided. Class 2 solvents are solvents to be limited inuse during the manufacture of the therapeutic agent. Class 3 solventsare solvents with low toxic potential and of lower risk to human health.Data for Class 3 solvents indicate that they are less toxic in acute orshort-term studies and negative in genotoxicity studies.

Class 1 solvents, which are to be avoided, include: benzene; carbontetrachloride; 1,2-dichloroethane; 1,1-dichloroethene; and1,1,1-trichloroethane.

Examples of Class 2 solvents are: acetonitrile, chlorobenzene,chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane,1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide,1,4-dioxane, 2-ethoxyethanol, ethyleneglycol, formamide, hexane,methanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane,N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin,toluene, 1,1,2-trichloroethene and xylene.

Class 3 solvents, which possess low toxicity, include: acetic acid,acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethylether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethylether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropylacetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone,methylisobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol,1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

Residual solvents in active pharmaceutical ingredients (APIs) originatefrom the manufacture of API. In most cases, the solvents are notcompletely removed by practical manufacturing techniques. Appropriateselection of the solvent for the synthesis of APIs may enhance theyield, or determine characteristics such as crystal form, purity, andsolubility. Therefore, the solvent is a critical parameter in thesynthetic process.

In some embodiments, compositions comprising Compound A-HCl include aresidual amount of an organic solvent(s). In some embodiments,compositions comprising Compound A-HCl comprise a residual amount of aClass 2 or Class 3 solvent. In some embodiments, compositions comprisingCompound A-HCl comprise a residual amount of a solvent selected fromethyl acetate, isopropyl acetate, tert-butylmethylether, heptane,isopropanol, methanol, acetone, dimethylformamide, tetrahydrofuran,1,4-dioxane, 2-methyltetrahydrofuran, toluene, and ethanol.

Unless otherwise stated, the following terms used in this applicationhave the definitions given below. The use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, or combinations thereof. Insome embodiments, a modulator is an agonist.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes ofadministration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds andcompositions described herein are administered orally.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered, which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is optionallydetermined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, and a co-agent, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g. acompound disclosed herein, or a pharmaceutically acceptable saltthereof, and a co-agent, are administered to a patient as separateentities either simultaneously, concurrently or sequentially with nospecific intervening time limits, wherein such administration provideseffective levels of the two compounds in the body of the patient. Thelatter also applies to cocktail therapy, e.g. the administration ofthree or more active ingredients.

The terms “article of manufacture” and “kit” are used as synonyms.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Pharmaceutical Compositions

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that are used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein is found, for example, inRemington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999),herein incorporated by reference for such disclosure.

In some embodiments, the compounds described herein are administeredeither alone or in combination with pharmaceutically acceptablecarriers, excipients or diluents, in a pharmaceutical composition.Administration of the compounds and compositions described herein can beeffected by any method that enables delivery of the compounds to thesite of action. These methods include, though are not limited todelivery via enteral routes (including oral) administration, althoughthe most suitable route may depend upon for example the condition anddisorder of the recipient.

In some embodiments, pharmaceutical compositions suitable for oraladministration are presented as discrete units such as capsules ortablets each containing a predetermined amount of the active ingredient;or as a powder or granules.

Pharmaceutical compositions which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. In some embodiments, the tabletsare coated or scored and are formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In some embodiments, stabilizers are added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets for identification or to characterize different combinations ofactive compound doses.

Conventional techniques to manufacture solid oral dosage forms include,but are not limited to, one or a combination of methods: (1) dry mixing,(2) direct compression, (3) milling, (4) dry or non-aqueous granulation,or (5) wet granulation. See, e.g., Lachman et al., The Theory andPractice of Industrial Pharmacy (1986). Other methods include, e.g.,spray drying, pan coating, melt granulation, granulation, fluidized bedspray drying or coating (e.g., wurster coating), tangential coating, topspraying, tableting, extruding and the like.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Provided herein are tablets comprising Compound A, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the tablet comprises:Compound A-HCl, or solvate thereof, dispersed in a polymer matrix formedfrom a pharmaceutically acceptable polymer; one or more pharmaceuticalacceptable ingredients selected from the group consisting of one or morediluents, one or more disintegrants, one or more lubricants, one or moreglidants; and optionally one or more film coating agents.

In some embodiments, described herein is a spray-dried solid dispersioncomprising (a) Compound A-HCl, or solvate thereof; and (b) apharmaceutically acceptable polymer; wherein Compound A-HCl, or solvatethereof, is dispersed in a polymer matrix formed from thepharmaceutically acceptable polymer.

In some embodiments, described herein are tablets prepared with thespray-dried solid dispersions described herein.

Spray-Dried Solid Dispersion (SDD)

The amorphous state for most small molecule drugs is thermodynamicallyunstable and, unless the glass transition temperature (Tg) issufficiently high, also kinetically unstable. However, the amorphousstate can be stabilized by dilution of the drug in an excipient matrix.When an amorphous molecule is dispersed in a high Tg matrix, lowmolecular mobility provides a diffusion barrier which inhibits molecularmobility that is required for phase separation upon storage. Phaseseparation into drug rich domains is the precursor to forming crystalnuclei and eventually widespread crystallization which results in a lostsolubility advantage. In some embodiments, pharmaceutically acceptablepolymers for use in preparing spray-dried solid dispersions are polymerswith a high Tg. In cases when the active pharmaceutical ingredient (API)and excipient are not thermodynamically miscible with one another in thesolid state, the spray-dried dispersion (SDD) is formulated such thatthe resulting Tg of the mixture, including absorbed water, is at least10° C. to 20° C. greater than typical storage conditions. Further,considerations must be made with respect to water uptake during storage,either through selection of a non-hygroscopic polymer or packagingconfiguration, as adsorbed water will plasticize the dispersion andlower the Tg.

In some embodiments, Compound A-HCl, or solvate thereof, in thespray-dried solid dispersions described herein is substantiallyamorphous.

In some embodiments, the pharmaceutically acceptable polymer comprisespolymers of: cellulose optionally functionalized with any combination ofalkyl ethers, alkyl esters, phthalate esters; vinyl alcohol; vinylacetate; propylene glycol; pyrrolidone; vinylpyrrolidone, oxyethylene;oxypropylene; methacrylic acid; methyl methacrylate; ethylene glycol;ethylene glycol glycerides; ethylene oxide; propylene oxide;2-ethyl-2-oxazoline; maleic acid; methyl vinyl ether; vinyl caprolactam;or combinations thereof.

In some embodiments, the pharmaceutically acceptable polymer ishydroxypropyl methylcellulose (HPMC), hydroxypropyl methyl celluloseacetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl celluloseacetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinylacetate copolymers, polyethylene glycol, polyethylene glycolpolypropylene glycol copolymers, polyvinylpyrrolidone (PVP),polyvinylpyrrolidone polyvinyl acetate copolymers (PVP/VA), polyethylenepolyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene blockcopolymers, cellulose acetate phthalate (CAP), hydroxypropylmethyl-cellulose phthalate (HPMCP), co-polymer of methacrylic acid andmethyl methacrylate, polyethylene glycol glycerides composed of mono-,di- and triglycerides and mono- and diesters of polyethylene glycol,hydroxypropylcellulose, copolymers of ethylene oxide and propylene oxideblocks, poly(2-ethyl-2-oxazoline), poly(maleic acid/methyl vinyl ether),polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graftcopolymer, ethylene oxide/propylene oxide tetra functional blockcopolymer, d-alpha tocopheryl polyethylene glycol 1000 succinate, orcombinations thereof.

In some embodiments, the spray-dried dispersion further comprises adispersion polymer. Dispersion polymers are selected from hydroxypropylmethylcellulose (HPMC), hypromellose acetate succinate (hydroxypropylmethyl cellulose acetate succinate; HPMCAS, such as HPMCAS-H, HPMCAS-L,or HPMCAS-M), hydroxypropyl cellulose (HPC), methyl cellulose,hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate,hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetatecopolymers, polyethylene glycol, polyethylene glycol polypropyleneglycol copolymers, polyvinylpyrrolidone (PVP), polyvinylpyrrolidonepolyvinyl acetate copolymers (PVP/VA), polyethylene polyvinyl alcoholcopolymers, polyoxyethylene-polyoxypropylene block copolymers, andcombinations thereof.

HPMCAS is a cellulosic polymer with four types of substituentssemirandomly substituted on the hydroxyls: methoxy, hydroxypropyloxy,acetate, and succinate. The polymer is available in three grades: L, Mand H, based on the content of acetyl and succinoyl groups (wt %) in theHPMCAS molecule. Grade L: 5-9% by weight acetate, 14-18% by weightsuccinate, 20-24% by weight methoxy, 5-9% by weight hydroxypropyloxy.Grade M: 7-11% by weight acetate, 10-14% by weight succinate, 21-25% byweight methoxy, 5-9% by weight hydroxypropyloxy. Grade H: 10-14% byweight acetate, 4-8% by weight succinate, 22-26% by weight methoxy,6-10% by weight hydroxypropyloxy.

In some embodiments, the pharmaceutically acceptable polymer is selectedfrom PVP/VA 64, PVP 30, HPMCAS-L, HPMCAS-M, HPMCAS-H, Eudragit L100-55,poly(methacrylic acid-co-methyl methacrylate)(PMMAMA, or trade nameEudragit L100), Eudragit EPO, HPMC E15, HPMC E3, HPMC E5, HPMCP-HP55,and Soluplus.

In some embodiments, the pharmaceutically acceptable polymer is selectedfrom PVP/VA 64 and HPMCAS-M. In some embodiments, the pharmaceuticallyacceptable polymer is PVP/VA 64. In some embodiments, thepharmaceutically acceptable polymer is HPMCAS-M.

In some embodiments, the weight ratio of Compound A-HCl, or solvatethereof, to the dispersion polymer is between about 1:10 and about 10:1.In some embodiments, the weight ratio of Compound A-HCl, or solvatethereof, to the dispersion polymer is between about 1:1 and about 1:10.In some embodiments, the weight ratio of Compound A-HCl, or solvatethereof, to the dispersion polymer is between about 1:3 and about 1:8.In some embodiments, the weight ratio of Compound A-HCl, or solvatethereof, to the dispersion polymer is between about 1:4 and about 1:7.In some embodiments, the weight ratio of Compound A-HCl, or solvatethereof, to the dispersion polymer is between about 1:4 and about 1:6.In some embodiments, the weight ratio of Compound A-HCl, or solvatethereof, to the dispersion polymer is between about 1:5 and about 1:6.In some embodiments, the weight ratio of Compound A-HCl, or solvatethereof, to the dispersion polymer is about 1:10. In some embodiments,the weight ratio of Compound A-HCl, or solvate thereof, to thedispersion polymer is about 1:9. In some embodiments, the weight ratioof Compound A-HCl, or solvate thereof, to the dispersion polymer isabout 1:8. In some embodiments, the weight ratio of Compound A-HCl, orsolvate thereof, to the dispersion polymer is about 1:7. In someembodiments, the weight ratio of Compound A-HCl, or solvate thereof, tothe dispersion polymer is about 1:6. In some embodiments, the weightratio of Compound A-HCl, or solvate thereof, to the dispersion polymeris about 1:5. In some embodiments, the weight ratio of Compound A-HCl,or solvate thereof, to the dispersion polymer is about 1:4. In someembodiments, the weight ratio of Compound A-HCl, or solvate thereof, tothe dispersion polymer is about 1:3. In some embodiments, the weightratio of Compound A-HCl, or solvate thereof, to the dispersion polymeris about 1:2. In some embodiments, the weight ratio of Compound A-HCl,or solvate thereof, to the dispersion polymer is about 1:1.

In some embodiments, the spray-dried solid dispersion comprises at least5% by weight of Compound A-HCl, or solvate thereof. In some embodiments,the spray-dried solid dispersion comprises at least 10% by weight ofCompound A-HCl, or solvate thereof. In some embodiments, the spray-driedsolid dispersion comprises at least 15% by weight of Compound A-HCl, orsolvate thereof. In some embodiments, the spray-dried solid dispersioncomprises at least 20% by weight of Compound A-HCl, or solvate thereof.In some embodiments, the spray-dried solid dispersion comprises at least25% by weight of Compound A-HCl, or solvate thereof. The % amounts arecalculated based on the free base, i.e. Compound A.

In some embodiments, the spray-dried solid dispersion comprises about5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%,about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, orabout 25% by weight of Compound A-HCl, or solvate thereof. In someembodiments, the spray-dried solid dispersion comprises about 5%, about6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%,about 33%, about 34%, or about 35% by weight of Compound A-HCl, orsolvate thereof. In some embodiments, the spray-dried solid dispersioncomprises about 15% of Compound A-HCl, or solvate thereof. In someembodiments, the spray-dried solid dispersion comprises about 35% ofCompound A-HCl, or solvate thereof. The % amounts are calculated basedon the free base, i.e. Compound A.

In some embodiments, the spray-dried solid dispersion comprises about 5%by weight of Compound A-HCl, or solvate thereof. In some embodiments,the spray-dried solid dispersion comprises about 6% by weight ofCompound A-HCl, or solvate thereof. In some embodiments, the spray-driedsolid dispersion comprises about 7% by weight of Compound A-HCl, orsolvate thereof. In some embodiments, the spray-dried solid dispersioncomprises about 8% by weight of Compound A-HCl, or solvate thereof. Insome embodiments, the spray-dried solid dispersion comprises about 9% byweight of Compound A-HCl, or solvate thereof. In some embodiments, thespray-dried solid dispersion comprises about 10% by weight of CompoundA-HCl, or solvate thereof. In some embodiments, the spray-dried soliddispersion comprises about 11% by weight of Compound A-HCl, or solvatethereof. In some embodiments, the spray-dried solid dispersion comprisesabout 12% by weight of Compound A-HCl, or solvate thereof. In someembodiments, the spray-dried solid dispersion comprises about 13% byweight of Compound A-HCl, or solvate thereof. In some embodiments, thespray-dried solid dispersion comprises about 14% by weight of CompoundA-HCl, or solvate thereof. In some embodiments, the spray-dried soliddispersion comprises about 15% by weight of Compound A-HCl, or solvatethereof. In some embodiments, the spray-dried solid dispersion comprisesabout 16% by weight of Compound A-HCl, or solvate thereof. In someembodiments, the spray-dried solid dispersion comprises about 17% byweight of Compound A-HCl, or solvate thereof. In some embodiments, thespray-dried solid dispersion comprises about 18% by weight of CompoundA-HCl, or solvate thereof. In some embodiments, the spray-dried soliddispersion comprises about 19% by weight of Compound A-HCl, or solvatethereof. In some embodiments, the spray-dried solid dispersion comprisesabout 20% by weight of Compound A-HCl, or solvate thereof. In someembodiments, the spray-dried solid dispersion comprises about 21% byweight of Compound A-HCl, or solvate thereof. In some embodiments, thespray-dried solid dispersion comprises about 22% by weight of CompoundA-HCl, or solvate thereof. In some embodiments, the spray-dried soliddispersion comprises about 23% by weight of Compound A-HCl, or solvatethereof. In some embodiments, the spray-dried solid dispersion comprisesabout 24% by weight of Compound A-HCl, or solvate thereof. In someembodiments, the spray-dried solid dispersion comprises about 25% byweight of Compound A-HCl, or solvate thereof. In some embodiments, thespray-dried solid dispersion comprises about 25% by weight of CompoundA-HCl, or solvate thereof. In some embodiments, the spray-dried soliddispersion comprises about 27% by weight of Compound A-HCl, or solvatethereof. In some embodiments, the spray-dried solid dispersion comprisesabout 28% by weight of Compound A-HCl, or solvate thereof. In someembodiments, the spray-dried solid dispersion comprises about 29% byweight of Compound A-HCl, or solvate thereof. In some embodiments, thespray-dried solid dispersion comprises about 30% by weight of CompoundA-HCl, or solvate thereof. In some embodiments, the spray-dried soliddispersion comprises about 31% by weight of Compound A-HCl, or solvatethereof. In some embodiments, the spray-dried solid dispersion comprisesabout 32% by weight of Compound A-HCl, or solvate thereof. In someembodiments, the spray-dried solid dispersion comprises about 33% byweight of Compound A-HCl, or solvate thereof. In some embodiments, thespray-dried solid dispersion comprises about 34% by weight of CompoundA-HCl, or solvate thereof. In some embodiments, the spray-dried soliddispersion comprises about 35% by weight of Compound A-HCl, or solvatethereof. The % amounts are calculated based on the free base, i.e.Compound A.

In some embodiments, the spray-dried solid dispersion further comprisesa non-aqueous solvent. In some embodiments, the non-aqueous solvent ispresent in detectable amounts. In some embodiments, the spray-driedsolid dispersion is non-aqueous solvent free.

In some embodiments, the spray-dried solid dispersion further comprisesa non-aqueous solvent selected from the group consisting oftert-butanol, n-propanol, n-butanol, isopropanol, ethanol, methanol,acetone, ethyl acetate, acetonitrile, methyl ethyl ketone, methylisobutyl ketone, methyl acetate, and mixtures thereof. In someembodiments, the spray-dried solid dispersion further comprises anon-aqueous solvent selected from the group consisting of methanol,acetone, and mixtures thereof. In some embodiments, the spray-driedsolid dispersion further comprises methanol.

Tablets

In one aspect, described herein is a tablet comprising: Compound A-HCl,or solvate thereof, dispersed in a polymer matrix formed from apharmaceutically acceptable polymer; one or more pharmaceuticalacceptable ingredients selected from the group consisting of one or morediluents, one or more disintegrants, one or more lubricants, one or moreglidants; and optionally one or more film coating agents.

In some embodiments, Compound A-HCl, or solvate thereof, dispersed in apolymer matrix formed from a pharmaceutically acceptable polymer is thespray-dried solid dispersion described herein.

In some embodiments, tablets comprise about 2% by weight to about 20% byweight of Compound A-HCl, or solvate thereof. In some embodiments,tablets comprise about 2% by weight to about 15% by weight of CompoundA-HCl, or solvate thereof.

In some embodiments, tablets comprise about 10% by weight to about 30%by weight of the polymer matrix formed from the pharmaceuticallyacceptable polymer. In some embodiments, tablets comprise about 20% byweight to about 35% by weight of the polymer matrix formed from thepharmaceutically acceptable polymer.

In some embodiments, tablets comprise about 2% by weight to about 10% byweight of Compound A-HCl, or solvate thereof, dispersed in about 10% byweight to about 30% by weight of a polymer matrix formed from apharmaceutically acceptable polymer.

In some embodiments, tablets comprise about 2% by weight to about 10% byweight of Compound A-HCl, or solvate thereof, dispersed in about 10% byweight to about 30% by weight of a polymer matrix formed from apharmaceutically acceptable polymer; about 40% by weight to about 80% byweight of one or more pharmaceutical acceptable ingredients selectedfrom the group consisting of one or more diluents, one or moredisintegrants, one or more lubricants, one or more glidants; andoptionally less than about 5% by weight of one or more film coatingagents.

In some embodiments, in addition to the spray-dried solid dispersion,additional excipients in the tablets comprise one or more diluents, oneor more disintegrants, one or more lubricants, one or more glidants, orany combination thereof. In some embodiments, in addition to thespray-dried solid dispersion, additional excipients in the tabletscomprise microcrystalline cellulose, mannitol, crospovidone, colloidalsilicon dioxide, and magnesium stearate.

In some embodiments, the tablet comprises one or morefillers/binders/diluents. Fillers/binders/diluents are selected fromcelluloses (such as microcrystalline cellulose, carboxymethylcellulose,ethyl cellulose and methyl cellulose), starch, gelatin, sugars (such assucrose, glucose, dextrose, mannitol, and lactose), natural andsynthetic gums (such as acacia, sodium alginate, panwar gum, and ghattigum), polyvinylpyrrolidinone, polyethylene glycol, waxes, and anycombinations thereof. In some embodiments, tablets comprisemicrocrystalline cellulose, and mannitol.

In some embodiments, the one or more fillers/binders/diluents in thetablets described herein comprise between about 20% and about 80% byweight of the total tablet weight. In some embodiments, the one or morefillers/binders/diluents in the tablets described herein comprisebetween about 40% and about 65% by weight of the total tablet weight. Insome embodiments, the one or more fillers/binders/diluents in thetablets described herein comprise between about 50% and about 65% byweight of the total tablet weight. In some embodiments, the one or morefillers/binders/diluents in the tablets described herein comprise about45%, about 50%, about 55%, about 60%, about 65%, or about 70% by weightof the total tablet weight. In some embodiments, the one or morefillers/binders/diluents in the tablets described herein comprise about58% by weight of the total tablet weight. In some embodiments, less than70% by weight, less than 65% by weight, less than 60% by weight, lessthan 55% by weight, or less than 50% by weight of the total tabletweight comprise one or more fillers/binders/diluents. In someembodiments, less than 60% by weight of the total tablet weight compriseone or more fillers/binders/diluents.

In some embodiments, tablets comprise one or more disintegrants.Disintegrants are selected from croscarmellose sodium, crospovidone,sodium starch glycolate, veegum HV, methylcellulose, agar, bentonite,cellulose, carboxymethyl cellulose, and any combination thereof. In someembodiments, tablets comprise crospovidone.

In some embodiments, the one or more disintegrants in the tabletsdescribed herein comprise between about 2% and about 30% by weight ofthe total tablet weight. In some embodiments, the one or moredisintegrants in the tablets described herein comprise between about 5%and about 20% by weight of the total tablet weight. In some embodiments,the one or more disintegrants in the tablets described herein comprisebetween about 10% and about 20% by weight of the total tablet weight. Insome embodiments, the one or more disintegrants in the tablets describedherein comprise about 5%, about 6%, about 7%, about 8%, about 9%, about10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,about 17%, about 18%, about 19%, or about 20% by weight of the totaltablet weight. In some embodiments, the one or more disintegrants in thetablets described herein comprise about 15% by weight of the totaltablet weight.

In some embodiments, less than 20% by weight of the total tablet weightcomprise one or more disintegrants.

In some embodiments, tablets comprise one or more lubricants. Lubricantsare selected from talc, magnesium stearate, calcium stearate, stearicacid, sodium stearyl fumarate, glyceryl behenate, hydrogenated vegetableoils, polyethylene glycol, and any combinations thereof. In someembodiments, tablets comprise magnesium stearate.

In some embodiments, the one or more lubricants in the tablets describedherein comprise between about 0.1% and about 5% by weight of the totaltablet weight. In some embodiments, the one or more lubricants in thetablets described herein comprise between about 0.1% and about 2% byweight of the total tablet weight. In some embodiments, the one or morelubricants in the tablets described herein comprise between about 0.1%and about 1% by weight of the total tablet weight. In some embodiments,the one or more lubricants in the tablets described herein compriseabout 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%,about 0.7%, about 0.8%, about 0.9%, or about 1% by weight of the totaltablet weight. In some embodiments, the one or more lubricants in thetablets described herein comprise about 0.5% by weight of the totaltablet weight. In some embodiments, less than 2% by weight of the totaltablet weight comprise one or more lubricants. In some embodiments, lessthan 1% by weight of the total tablet weight comprise one or morelubricants.

In some embodiments, tablets comprise one or more glidants. A glidant isa substance that is added to a powder to improve its flowability.Examples of glidants include magnesium stearate, colloidal silicondioxide, starch and talc. In some embodiments, tablets comprisecolloidal silicon dioxide.

In some embodiments, the one or more lubricants in the tablets describedherein comprise between about 0.1% and about 5% by weight of the totaltablet weight. In some embodiments, the one or more lubricants in thetablets described herein comprise between about 0.1% and about 2% byweight of the total tablet weight. In some embodiments, the one or morelubricants in the tablets described herein comprise between about 0.5%and about 1.5% by weight of the total tablet weight. In someembodiments, the one or more lubricants in the tablets described hereincomprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%,about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%,about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%,about 1.8%, about 1.9%, or about 2% by weight of the total tabletweight. In some embodiments, the one or more lubricants in the tabletsdescribed herein comprise about 1% by weight of the total tablet weight.In some embodiments, less than 2% by weight of the total tablet weightcomprise one or more lubricants. In some embodiments, less than 1.5% byweight of the total tablet weight comprise one or more lubricants.

Additional Excipients

In some embodiments, the tablet described herein comprises additionalexcipients including, but not limited, to buffering agents, glidants,preservatives, and coloring agents. Additional excipients such asbulking agents, tonicity agents, and chelating agents are within thescope of the embodiments.

Non-limiting examples of buffering agents include, but are not limitedto, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide,magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminumhydroxide/sodium bicarbonate co precipitate, a mixture of an amino acidand a buffer, a mixture of aluminum glycinate and a buffer, a mixture ofan acid salt of an amino acid and a buffer, and a mixture of an alkalisalt of an amino acid and a buffer. Additional buffering agents includesodium citrate, sodium tartarate, sodium acetate, sodium carbonate,sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate,potassium pyrophosphate, disodium hydrogenphosphate, dipotassiumhydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodiumacetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide,magnesium carbonate, magnesium silicate, calcium acetate, calciumglycerophosphate, calcium chloride, calcium hydroxide, calcium lactate,calcium carbonate, calcium bicarbonate, and other calcium salts.

In some embodiments, the tablet described herein comprises apreservative. Preservatives include anti-microbials, anti-oxidants, andagents that enhance sterility. Exemplary preservatives include ascorbicacid, ascorbyl palmitate, BHA, BHT, citric acid, erythorbic acid,fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodiumbisulfate, sodium metabisulfite, sodium sulfite, parabens (methyl-,ethyl-, butyl-), benzoic acid, potassium sorbate, vanillin, and thelike.

In some embodiments, the tablet described herein comprises a coloringagent for identity and/or aesthetic purposes of the resultant liquidform. Suitable coloring agents illustratively include FD&C Red No. 3,FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2,D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide and mixturesthereof.

Additional excipients are contemplated in the tablet embodiments. Theseadditional excipients are selected based on function and compatibilitywith the tablet compositions described herein and may be found, forexample in Remington: The Science and Practice of Pharmacy, NineteenthEd (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, (Easton, Pa.: Mack Publishing Co1975); Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms (New York, N.Y.: Marcel Decker 1980); and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed (Lippincott Williams &Wilkins 1999), herein incorporated by reference in their entirety.

In further embodiments, the tablets described herein are coated tablets,such as enteric-coated tablets, sugar-coated, or film-coated tablets.

In one embodiment, the individual unit dosages also include filmcoatings, which disintegrate upon oral ingestion or upon contact withdiluent. In one embodiment, these formulations are manufactured byconventional techniques.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating aids in patient compliance(e.g., Opadry® coatings or sugar coating). Film coatings comprisingOpadry® typically range from about 1% to about 5% of the tablet weight.In other embodiments, the compressed tablets include one or moreexcipients.

Provided herein are film-coated tablets forms, which comprise: acombination of an active ingredient (e.g. Compound A-HCl) and one ormore tabletting excipients to form a tablet core and subsequentlycoating the core. The tablet cores are produced using conventionaltabletting processes and with subsequent compression and coating.

Enteric-coatings are coatings that resist the action of stomach acid butdissolve or disintegrate in the intestine.

In one aspect, the oral solid dosage form disclosed herein include anenteric coating(s). Enteric coatings include one or more of thefollowing: cellulose acetate phthalate; methyl acrylate-methacrylic acidcopolymers; cellulose acetate succinate; hydroxy propyl methyl cellulosephthalate; hydroxy propyl methyl cellulose acetate succinate(hypromellose acetate succinate); polyvinyl acetate phthalate (PVAP);methyl methacrylate-methacrylic acid copolymers; methacrylic acidcopolymers, cellulose acetate (and its succinate and phthalate version);styrol maleic acid copolymers; polymethacrylic acid/acrylic acidcopolymer; hydroxyethyl ethyl cellulose phthalate; hydroxypropyl methylcellulose acetate succinate; cellulose acetate tetrahydrophtalate;acrylic resin; shellac.

An enteric coating is a coating put on a tablet, pill, capsule, pellet,bead, granule, particle, etc. so that it doesn't dissolve until itreaches the small intestine.

Sugar-coated tablets are compressed tablets surrounded by a sugarcoating, which may be beneficial in covering up objectionable tastes orodors and in protecting the tablets from oxidation.

Film-coated tablets are compressed tablets that are covered with a thinlayer or film of a water-soluble material. Film coatings include, butare not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. Film coating imparts the same general characteristics assugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets. In some embodiments, tablets arecoated with water soluble, pH independent film coating which allows forimmediate disintegration for fast, active release (e.g. Opadryproducts).

Dosage in the Tablet

In some embodiments, the amount of Compound A-HCl, or solvate thereof,in the tablet is between about 5 mg and about 100 mg. In someembodiments, the amount of Compound A-HCl, or solvate thereof, in thetablet is between about 5 mg and about 80 mg. In some embodiments, theamount of Compound A-HCl, or solvate thereof, in the tablet is betweenabout 5 mg and about 60 mg. In some embodiments, the amount of CompoundA-HCl, or solvate thereof, in the tablet is between about 10 mg andabout 40 mg.

In some embodiments, the amount of Compound A-HCl, or solvate thereof,in the tablet is about 10 mg. In some embodiments, the amount ofCompound A-HCl, or solvate thereof, in the tablet is about 20 mg. Insome embodiments, the amount of Compound A-HCl, or solvate thereof, inthe tablet is about 30 mg. In some embodiments, the amount of CompoundA-HCl, or solvate thereof, in the tablet is about 40 mg. In someembodiments, the amount of Compound A-HCl, or solvate thereof, in thetablet is about 50 mg. In some embodiments, the amount of CompoundA-HCl, or solvate thereof, in the tablet is about 60 mg. In someembodiments, the amount of Compound A-HCl, or solvate thereof, in thetablet is about 70 mg. In some embodiments, the amount of CompoundA-HCl, or solvate thereof, in the tablet is about 80 mg.

Methods of Dosing and Treatment Regimens

In one embodiment, the pharmaceutical compositions disclosed herein areused as medicaments for the treatment of diseases or conditions in amammal that would benefit from modulation of somatostatin activity.Methods for treating any of the diseases or conditions described hereinin a mammal in need of such treatment, involves administration ofpharmaceutical compositions that include Compound A, or apharmaceutically acceptable salt thereof, in therapeutically effectiveamounts to said mammal.

In certain embodiments, the compositions containing Compound A describedherein are administered for prophylactic and/or therapeutic treatments.In certain therapeutic applications, the compositions are administeredto a patient already suffering from a disease or condition, in an amountsufficient to cure or at least partially arrest at least one of thesymptoms of the disease or condition. Amounts effective for this usedepend on the severity and course of the disease or condition, previoustherapy, the patient's health status, weight, and response to the drugs,and the judgment of the treating physician. Therapeutically effectiveamounts are optionally determined by methods including, but not limitedto, a dose escalation and/or dose ranging clinical trial.

In general, however, doses employed for adult human treatment aretypically in the range of about 10 mg to about 100 mg per day ofCompound A. In one embodiment, the desired dose is convenientlypresented in a single dose or in divided doses administeredsimultaneously or at appropriate intervals, for example as two, three,four or more sub-doses per day.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which the compound is administered oncea day.

EXAMPLES

The following examples are provided for illustrative purposes only andnot to limit the scope of the claims provided herein.

Example 1: Oral Capsules

Representative capsules are described below in Table 1.

TABLE 1 Quantity per Component Name Function Unit (mg) % w/w CompoundA-HCl^(a) Drug substance 10.00 5.00 Microcrystalline Cellulose Diluent85.5 42.77 Mannitol Diluent 85.5 42.77 Croscarmellose SodiumDisintegrant 7.4 3.70 Vitamin E Polyethylene Glycol Solubilizer 8.5 4.27Succinate (TPGS) Colloidal Silicon Dioxide Glidant 2.0 1.00 SodiumStearyl Fumarate Lubricant 1.0 0.50 Size 2 Gelatin Capsule^(c) CapsuleShell NA NA Total 200.00^(b) 100.00 ^(a)Amount corrected for assay andmoisture, chloride and isopropyl alcohol content; ^(b)Capsule fillweight adjusted based upon blend assay; ^(c)Composed of red iron oxide,titanium dioxide and gelatin.

A representative description of the manufacturing process for the hotmelt granulation capsules is as follows:

Stage 1: High Shear Wet Granulation: Melt the Vitamin E PolyethyleneGlycol Succinate (TPGS). Compound A-HCl, mannitol, microcrystallinecellulose, croscarmellose sodium and silicon dioxide are charged into ahigh shear wet granulator and mixed. The melted Vitamin E TPGS issprayed onto the granulation components.

Stage 2: Milling: The wet granulation is milled through a screening millusing an appropriately sized screen.

Stage 3: Blending: The sodium stearyl fumarate is sieved using anappropriately sized screen. The milled granulation is charged into thediffusion mixer (tumble) along with the sodium stearyl fumarate andblended.

Stage 4: Encapsulation: The 10 mg capsules were automaticallyencapsulated in Size 2 gelatin capsules.

Example 2: Spray-Dried Solid Dispersions

Spray-dried solid dispersions were prepared with 15% by weight CompoundA-HCl: 15/85 Compound A-HCl/HPMCAS-M and 15/85 Compound A-HCl/PVP VA64formulations. The manufactures were completed using the BLD-150, theBend Lab Dryer with 150 kg/hr drying gas capacity. The parameters variedwere solution solids loading for the HPMCAS-M SDD formulation to helpreduce nozzle bearding, and dryer outlet temperature for the PVP VA64SDD to de-risk fluctuations that may occur during clinicalmanufacturing. The original process parameter screening plan specifiedmanufacturing the decreased dryer outlet temperature condition with alarger orifice nozzle to produce larger particles, however based on theresults of the first spray it was determined that the atomizationpressure needed to achieve the desired solution flow rate would havebeen too low to fully atomize the solution with the larger orifice. Asdryer outlet temperature tends to have more variability than solutionflow rate, the parameter screen was shifted to focus on de-risking thedryer outlet temperature alone while ensuring fully atomized droplets.Dryer outlet temperature variation could affect residual solvent levelsin the SDDs, which can affect physical and chemical stability. Allsprays were completed successfully with good yields, and indicate arobust processing space for both formulations.

15/85 Compound a HPMCAS-M SDD Formulation Manufacturing Details

Three sub batches of 15/85 Compound A-HCl/HPMCAS-M SDDs were sprayed toexplore the manufacture processing space and prepare for clinical trialmanufacturing. A sub batch was sprayed first at 10 wt % solids, andsignificant nozzle bearding that appeared to affect the spray plume wasobserved after about 45 minutes on solution.

The solution was diluted to 8 wt %, and a sub batch was manufacturedwith a duration of 1 hour to ensure bearding was reduced. A very smallamount of bearding was observed during this batch after about 50 minuteson solution, but did not appear to affect the atomization plume and the8 wt % solids loading was selected.

Cooling water at 2 GPM and approximately 7° C. was run through the spraydryer lid throughout all sprays to keep the lid cool and preventsticking and browning. No significant lid buildup or browning was seenthroughout manufacturing. No cleaning was performed between sprays, andall sprays were completed from one solution with additional solventadded prior to manufacturing batches 2A and 2C. A summary of themanufacturing parameters used for all three sub batches is shown inTable 2.

TABLE 2 Manufacturing summary for 15/85 Compound A-HCl/HPMCAS-M SDDs.Parameter Lot 2A Lot 2B Lot 2C Bulk SDD collected (g) 5316 2231 624Solids loading in solution (wt %) 8 10 8 Solvent Methanol AtomizerPressure swirl: Steinen A75 Atomizing pressure (psig) 370 301 345Solution flow (g/min) 131 132 131 Drying gas flow rate (g/min) 1848 18481848 Dryer inlet temperature (° C.) 146 145 144 Dryer outlet temperature(° C.) 45 45 45 Bulk secondary tray drying 16 hours at 17 hours at 40°C./15% RH 40° C./15% RH Dry yield (%)¹ 96 96 93 Spray duration (hours) 83 1 Calculated dryer relative saturation 11 (%) Calculated dew point (°C.) 3 ¹Dry yield is calculated as SDD samples and dry bulk collecteddivided by the amount of solids sprayed.

15/85 Compound A-HCl/PVP VA64 SDD Formulation Manufacturing Details

Process parameter screening sprays and an FPN demonstration batch werealso completed for the 15/85 Compound A-HCl/PVP VA64 SDD formulation.The dryer outlet temperature was varied to de-risk process parametervariability to prepare for clinical trial manufacturing.

The process space was constrained by a maximum dryer outlet temperature,the dryer outlet temperature, and the minimum desired solution flowrate. A maximum inlet temperature of 160° C. was specified to avoidsticking or browning of SDD on the spray dryer lid, and the minimum flowrate was set at 100 g/min to ensure sufficient throughput. The minimumand maximum dryer outlet temperatures were chosen to be 40° C. and 65°C. respectively to ensure adequate particle drying and that the dryeroutlet temperature will not be above the wet particle Tg.

The process parameter screening sprays for the PVP VA64 formulationexplored the manufacturing space by varying the dryer outlettemperature. This allowed investigation of the effect of dryer relativesaturation on particle residual solvent content, morphology, density,and stability.

Cooling water was run at 2 GPM and approximately 7° C. throughout allsprays to prevent lid buildup and browning, and neither were noted. Nonozzle bearding was observed throughout all three manufactures. Allsprays were completed from one solution. The manufacturing details ofeach sub batch are summarized in Table 3.

TABLE 3 15/85 Compound A-HCl*/PVP VA64 SDD process parameters ParameterLot 4A Lot 4B Lot 4C Bulk SDD collected (g) 5285 623 624 Solids loadingin solution (wt %) 8 Solvent Methanol Atomizer Pressure swirl: SteinenA75 Atomizing pressure (psig) 422 449 445 Solution flow (g/min) 128 133132 Drying gas flow rate (g/min) 1845 1848 1849 Dryer inlet temperature(° C.) 143 153 132 Dryer outlet temperature (° C.) 45 49 40 Bulksecondary tray drying 18 hours at 26 hours at 40° C./15% RH 40° C./15%RH Dry yield (%)¹ 92 86 91 Spray duration (hours) 8 1 1 Calculated dryerrelative saturation 11 9 14 (%) Calculated dew point (° C.) 3 *CompoundA-HCl, formulated on a basis of free base. ¹Dry yield is calculated asSDD samples and dry bulk collected divided by the amount of solidssprayed.

SDD Characterization

Particle Properties: The particle size distribution and bulk and tappeddensities were measured for each batch of Compound A-HCl SDD. TheHPMCAS-M SDDs have larger particle sizes, which is expected because theHPMCAS-M solution is more viscous than the PVP VA64 solution which leadsto larger droplets for a given nozzle configuration. The increasedsolids loading in solution of lot 2B led to larger particles thanbatches 2A and 2C, which is also due to the higher viscosity of thespray solution. The particle size distributions of all PVPVA-64 batchesare similar, as expected.

The bulk and tapped densities of 2A and 2C are similar, while batch 2Bhas a slightly lower density potentially due to the larger particles.The bulk and tapped densities of all PVPVA-64 batches are similar,indicating a robust process with respect to the dryer outlet temperatureeffects on powder properties.

Residual Solvent and Water Content: The residual methanol and water ofthe six SDDs were measured using GC and KF respectively. All SDDscontained residual methanol below the ICH guideline of 0.3 wt % aftersecondary drying, suggesting adequate drying at 40° C./15% RH.

Morphology by SEM: The particle morphology of all six SDDs was evaluatedvia SEM. Each SDD showed typical morphology with no evidence ofirregular particles suggesting adequate atomization for all conditionstested. The HPMCAS-M particles were primarily collapsed spheres whilethe PVP VA64 SDDs contain a larger fraction of spherical particles.

Crystallinity by PXRD: All six SDDs were evaluated for crystallinityusing PXRD. All SDDs were amorphous by PXRD as evident in the absence ofsharp diffraction peaks.

Thermal Characteristics by DSC: All six SDDs were characterized bymodulated DSC. The results are tabulated in Table 4. The manufacturedSDDs were all amorphous and homogenous by DSC as evident by the presenceof a single glass transition in the reversing heat signal. Neitherformulation shows signs of crystallization after the Tg suggesting lowpropensity for crystallization of Compound A at those temperatures forboth formulations. Furthermore, both formulations showed high Tgrelative to ambient temperatures suggesting low physical stability risksin dry conditions. Packaging to minimize humidity will be necessary forthe PVP VA64 formulation.

TABLE 4 Tabulated thermal characteristics of the six batches as measuredby DSC. Tg Std Delta Cp Std Sample Lot (° C.) Dev* (J/(g*° C.)) Dev*15/85 Compound A- 2A 135.2 0.35 0.27 0.03 HCl/HPMCAS-M SDD 2B 134.7 0.360.25 0.02 2C* 134.5 0.95 0.26 0.00 15/85 Compound A- 4A* 125.5 0.04 0.310.01 HCl/PVP VA64 SDD 4B 125.6 0.26 0.30 0.01 4C 125.6 0.17 0.35 0.08*Average is from n = 2 replicates. As a result, std deviation isactually calculated as range/2.

Summary

Physical Stability observations: PVP VA64 SDD appeared to deliquesceupon storage with crystals observed at 3 months (40° C./75% RH open).Storage with desiccant is recommended. HPMCAS-M SDD was physicallystable through 6 months at 40° C./75% RH open.

Chemical Stability observations: Possible acid catalyzed degradation inthe HPMCAS-M formulation on stability. Some degradation in the PVP VA64formulation as well, but not as significant as the HPMCAS-M SDD.Packaging will be required for the PVPVA SDD which will be driven byphysical stability concerns.

The 15% by weight Compound A/PVP VA64 was selected as the lead SDDformulation.

12-Month Stability: 15% Compound A-HCl/PVP-VA64 SDD

12-month SDD samples were held at 5° C., 25° C./60% RH, and 40° C./75%RH with desiccant. Samples for water analysis by Karl Fisher titrationwere prepared and analyzed immediately; the remaining samples werevacuum desiccated overnight to remove residual moisture and preserve thephysical state of SDD's for further characterization. A list of theanalytical tests performed for characterization included: appearance,water content by Karl Fisher titration, Powder x-ray diffraction (PXRD),scanning electron microscopy (SEM), thermal characterization bymodulated differential scanning calorimetry (mDSC), dissolutionperformance by micro-centrifuge (MCT) test, assay and related substancesby HPLC.

Conclusion from PXRD analysis on the 12-month SDD stability samples:There was no evidence of crystallinity in samples stored at 12 months ateach of the stability conditions.

Conclusion from SEM analysis on the 12-month SDD stability samples: Noparticle fusion was observed across all stability conditions at 12month. There was no evidence of crystallinity in samples stored at 12months at each of the stability conditions.

Conclusion from SEM analysis on the 12-month SDD stability samples: Noparticle fusion is observed across all stability conditions at 12months. There was no evidence of crystallinity in samples stored at 12months at each of the stability conditions.

Conclusions from mDSC analysis on the 12-month SDD stability samples:Repeated analysis of the 12 month SDD sample held at 5° C. affordsnon-reproducible thermograms, the cause for this result is not known atthis time. The 5° C. sample was determined to be physically stable byall other characterization techniques. The 12 month SDD samples held at25° C./60% RH and 40° C./75% RH showed a single, reproducible Tg at124-125° C., supporting the conclusion that the SDD is stable after 12months of storage with desiccant at these conditions.

Conclusion from MCT dissolution analysis on the 12-month SDD stabilitysamples: Non-sink dissolution performance of the 12 month stabilitysamples is consistent with the initial (to) sample stored at −20° C.

35/65 Compound A-HCl/PVP VA64 SDD Formulation Manufacturing Details

Spray-dried solid dispersions were prepared with 35% by weight CompoundA-HCl: 35/65 Compound A-HCl/PVP VA64 formulation.

The manufacture of the SDD was completed using the SD-180 lab dryer.Secondary drying was completed using the Binder Convection Dryer. Themanufacturing details are summarized in Table 5.

The spray was completed successfully with good yield.

TABLE 5 35/65 Compound A-HCl*/PVP VA64 SDD process parameters ParameterValue Bulk SDD collected (g) 2796 Solids loading in solution (wt %) 10.8Solvent Methanol Atomizer SD-90 with Pressure Swirl Atomizing pressure(psig) 320 Solution flow (g/min) 115 Drying gas rate (acfm) 80 Dryerinlet temperature (° C.) 100 Dryer outlet temperature (° C.) 45Condensore Setpoint (° C.) −20 Bulk secondary tray drying 48 hours at40° C./ ambient pressure *Compound A-HCl, formulated on a basis of freebase

Example 3: Oral Tablets

Representative 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg spray-drieddispersion tablets are presented in Tables 6, 7, 8, 9, 10, 11, 12, and13.

Typical excipients used to prepare the tablets included:microcrystalline cellulose, mannitol, crospovidone, colloidal silicondioxide, magnesium stearate, and Opadry White 03K184116 (film coating).

TABLE 6 Representative 10 mg spray-dried dispersion tablets. Quantityper Component Name Function Unit (mg) % w/w Spray-Dried DispersionCompound A-HCl Drug substance 10.00 3.20 PVP/VA 64 Film Forming 56.6718.15 Agent Methanol^(a) Solvent NA NA Roller Compaction/BlendingMicrocrystalline Cellulose Diluent 130.31 41.74 Mannitol Diluent 53.0416.99 Crospovidone Disintegrant 30.29 9.71 Colloidal Silicon DioxideGlidant 1.53 0.49 Magnesium Stearate Lubricant 0.76 0.24Blending/Compression Crospovidone Disintegrant 18.18 5.82 ColloidalSilicon Dioxide Glidant 1.52 0.49 Magnesium Stearate Lubricant 0.76 0.24Film Coating Opadry ® White 03K18416^(b) Film Coating 9.09 2.91 AgentPurified Water^(c) Solvent NA NA Total 312.15 100.0 ^(a)Methanol removedon drying during the spray drying process. ^(b)Composed of Hypromellose2910, titanium dioxide and triacetin. ^(c)Purified water removed ondrying during the film coating process.

TABLE 7 Representative 20 mg spray-dried dispersion (HPMCAS-M) tablets.Formulation no. A1 A2 A3 Tablet Dose/ Tablet Weight (mg/mg) 20/40020/400 20/400 Function Ingredient % w/w of Blend Pregranulation Active15/85 Compound A- 33.33%  33.33%  33.33%  HCl/HPMCAS-M Local PH CitricAcid — — 5.00% Modifier Filler Microcrystalline 38.11%  40.11%  36.78% Cellulose (Avicel PH-102) Filler Mannitol (Mannogem EZ 19.06%  20.06% 18.39%  Spray Dried) Disinte- Sodium Chloride (NaCl — — — grationPowder) Aid Disinte- Sodium Starch Glycolate 5.00% — — grant (Explotab)Disinte- Crospovidone (PVP-XL) — 5.00% 3.00% grant Glidant Silicondioxide (Syloid 0.50% 0.50% 0.50% 244 FP) Lubricant Magnesium Stearate0.25% 0.25% 0.25% Extragranular Disinte- Sodium Starch Glycolate 3.00% —— grant (Explotab) Disinte- Crospovidone (PVP-XL) — — 2.00% grantGlidant Silicon dioxide (Syloid 0.50% 0.50% 0.50% 244 FP) LubricantMagnesium Stearate 0.25% 0.25% 0.25%

TABLE 8 Representative 20 mg spray-dried dispersion (PVPVA 64) tablets.Formulation no. B1 B2 B3 Tablet Dose/ Tablet Weight (mg/mg) 20/40020/400 20/400 Function Ingredient % w/w of Blend Pregranulation Active15/85 Compound A- 33.33%  33.33%  33.33%  HCl/PVPVA 64 Local PH CitricAcid 5.00% — — Modifier Filler Microcrystalline 43.17%  33.17%  33.17% Cellulose (Avicel PH-102) Filler Mannitol (Mannogem EZ — 20.00%  — SprayDried) Disinte- Sodium Chloride (NaCl 5.00% — 20.00%  gration Powder)Aid Disinte- Sodium Starch Glycolate 6.00% — — grant (Explotab) Disinte-Crospovidone (PVP-XL) — 6.00% 6.00% grant Glidant Silicon dioxide(Syloid 0.50% 0.50% 0.50% 244 FP) Lubricant Magnesium Stearate 0.25%0.25% 0.25% Extragranular Disinte- Sodium Starch Glycolate 6.00% — —grant (Explotab) Disinte- Crospovidone (PVP-XL) — 6.00% 6.00% grantGlidant Silicon dioxide (Syloid 0.50% 0.50% 0.50% 244 FP) LubricantMagnesium Stearate 0.25% 0.25% 0.25%

TABLE 9 Additional representative 20 mg spray dried dispersion tablets.Formulation no. A4 B4 B5 B6 Tablet Dose/ Tablet Weight (mg/mg) 20/ 20/20/ 20/ 400 606.1 400 606.1 Function Ingredient % w/w of BlendPregranulation Active 15/85 Compound A- 33.33% — — — HCl/HPMCAS-M Active15/85 Compound A- — 22.00% 33.33% 22.00% HCl/PVPVA 64 Local PH CitricAcid 5.00% 5.00% — — Modifier Filler Microcrystalline 35.61% 40.50%33.17% 43.00% Cellulose (Avicel PH-102) Filler Mannitol (Mannogem 16.56%15.00% 16.00% 17.50% EZ Spray Dried) Disinte- Crospovidone (PVP- 5.00%10.00% 10.00% 10.00% grant XL) Glidant Silicon dioxide (Syloid 0.50%0.50% 0.50% 0.50% 244 FP) Lubricant Magnesium Stearate 0.25% 0.25% 0.25%0.25% Extragranular Disinte- Crospovidone (PVP- 3.00% 6.00% 6.00% 6.00%grant XL) Glidant Silicon dioxide (Syloid 0.50% 0.50% 0.50% 0.50% 244FP) Lubricant Magnesium Stearate 0.25% 0.25% 0.25% 0.25%

TABLE 10 Representative 30 mg and 40 mg spray- dried dispersion (PVPVA64) tablets. Formulation no. D1 D2 Tablet Dose/ Tablet Weight (mg/mg)30/909.2 40/1212.3 Function Ingredient % w/w of Blend Active 15/85Compound A-HCl/ 22.00 22.00 PVPVA 64 Filler Microcrystalline Cellulose43.00 43.00 (Avicel PH-101) Filler Mannitol (Parteck M100) 17.50 17.50Disintegrant Crospovidone (PVP-XL) 10.00 10.00 Glidant Silicon dioxide(Syloid 0.50 0.50 244 FP) Lubricant Magnesium Stearate 0.25 0.25Disintegrant Crospovidone (PVP-XL) 6.00 6.00 Glidant Silicon dioxide(Syloid 0.50 0.50 244 FP) Lubricant Magnesium Stearate 0.25 0.25

TABLE 11 Additional representative 40 mg spray- dried dispersion (PVPVA64) tablets. Formulation no. E1 E2 E3 Tablet Dose/ Tablet Weight (mg/mg)40/500 40/600 40/600 Function Ingredient % w/w of Blend PregranulationActive 35/65 Compound A-HCl/ 34.29% 28.57% 28.57% PVPVA 64 FillerMicrocrystalline Cellulose 32.14% 28.18% 22.18% (Avicel PH-101) FillerMannitol (Parteck M100) 16.07% 14.09% 11.09% Disintegrant CroscarmelloseSodium 5.00% 5.00% 7.81% (Ac-Di-Sol) Disintegrant Crospovidone (PVP-XL)5.00% 5.00% 7.81% Glidant Silicon dioxide (Syloid 0.50% 0.50% 0.50% 244FP) Lubricant Magnesium Stearate 0.25% 0.25% 0.25% Extragranular FillerMicrocrystalline Cellulose — 11.67% 11.67% (Avicel PH-101) DisintegrantCroscarmellose Sodium 3.00% 3.00% 4.69% (Ac-Di-Sol) DisintegrantCrospovidone (PVP-XL) 3.00% 3.00% 4.69% Glidant Silicon dioxide (Syloid0.50% 0.50% 0.50% 244 FP) Lubricant Magnesium Stearate 0.25% 0.25% 0.25%

TABLE 12 Representative 60 mg spray-dried dispersion (PVPVA 64) tablets.Formulation no. C1 C2 C3 Tablet Dose/ Tablet Weight (mg/mg) 60/50060/600 60/600 Function Ingredient % w/w of Blend Pregranulation Active35/65 Compound A-HCl/ 34.29% 28.57% 28.57% PVPVA 64 FillerMicrocrystalline Cellulose 32.14% 28.18% 22.18% (Avicel PH-101) FillerMannitol (Parteck M100) 16.07% 14.09% 11.09% Disintegrant CroscarmelloseSodium 5.00% 5.00% 7.81% (Ac-Di-Sol) Disintegrant Crospovidone (PVP-XL)5.00% 5.00% 7.81% Glidant Silicon dioxide (Syloid 0.50% 0.50% 0.50% 244FP) Lubricant Magnesium Stearate 0.25% 0.25% 0.25% Extragranular FillerMicrocrystalline Cellulose — 11.67% 11.67% (Avicel PH-101) DisintegrantCroscarmellose Sodium 3.00% 3.00% 4.69% (Ac-Di-Sol) DisintegrantCrospovidone (PVP-XL) 3.00% 3.00% 4.69% Glidant Silicon dioxide (Syloid0.50% 0.50% 0.50% 244 FP) Lubricant Magnesium Stearate 0.25% 0.25% 0.25%

TABLE 13 Additional representative 60 mg spray- dried dispersion (PVPVA64) tablets. Formulation no. C4 C5 C6 Tablet Dose/ Tablet Weight (mg/mg)60/ 60/ 60/ 600 600 600 Function Ingredient % w/w of BlendPregranulation Active 35/65 Compound A-HCl/ 28.57% 28.57% 28.57% PVPVA64 Filler Microcrystalline Cellulose 15.08% 18.41% 18.41% (AvicelPH-101) Filler Mannitol (Parteck M100) 7.54% 9.21% 9.21% DisintegrantPregelatinized Starch (Starch 20.00% — — 1500) Disinte- Sodium Chloride(NaCl — 10.00% — gration Aid Powder) Disinte- 1:1 Sodium Chloride:Potas-— — 10.00% gration Aid sium Chloride Disintegrant Croscarmellose Sodium(Ac- 5.00% 5.00% 5.00% Di-Sol) Disintegrant Crospovidone (PVP-XL) 5.00%5.00% 5.00% Glidant Silicon dioxide (Syloid 244 0.50% 0.50% 0.50% FP)Lubricant Magnesium Stearate 0.25% 0.25% 0.25% Extragranular FillerMicrocrystalline Cellulose 11.31% 11.31% 11.31% (Avicel PH-101)Disintegrant Croscarmellose Sodium (Ac- 3.00% 3.00% 3.00% Di-Sol)Disintegrant Crospovidone (PVP-XL) 3.00% 3.00% 3.00% Glidant Silicondioxide (Syloid 244 0.50% 0.50% 0.50% FP) Disinte- Sodium Chloride (NaCl— 5.00% — gration Aid Powder) Disinte- 1:1 Sodium Chloride:Potas- — —5.00% gration Aid sium Chloride Lubricant Magnesium Stearate 0.25% 0.25%0.25%

TABLE 14 Exemplary spray-dried dispersion tablets. % w/w FunctionExemplary Ingredients of Tablet Pregranulation Active (SDD) 15/85Compound A-HCl/HPMCAS-M, 20 to 35% 15/85 Compound A-HCl/PVPVA 64, or35/65 Compound A-HCl/PVPVA 64 Filler(s) Microcrystalline Cellulose, 20to 60% Mannitol Disintegrant(s) Pregelatinized Starch, 5 to 30%Croscarmellose Sodium, Crospovidone Disintegration Sodium Chloride (NaClPowder), 0 to 10% Aid(s) 1:1 Sodium Chloride:Potassium Chloride GlidantSilicon dioxide 0.25 to 1% Lubricant Magnesium Stearate 0.25 to 1% TotalPregranulation 70% to 85% Extragranular Filler(s) MicrocrystallineCellulose 0 to 20% Disintegrant(s) Croscarmellose Sodium, 3 to 10%Crospovidone Disintegration Sodium Chloride (NaCl Powder), 0 to 5%Aid(s) 1:1 Sodium Chloride:Potassium Chloride Glidant Silicon dioxide0.25 to 1% Lubricant Magnesium Stearate 0.25 to 1% Total Extragranular15 to 30%

A representative non-limiting description of the manufacturing processfor the SDD tablets is as follows:

Stage 1: Spray Drying: Compound A-HCl and copovidone are dissolved inMeOH. The solution spray-dried. Spray-dried dispersion (Compound A-HClSDD) is collected.

Stage 2: Roller Compaction: Granulation blend consisting of CompoundA-HCl SDD, filler(s), disintegrant(s), glidant(s), and lubricant(s) areblended. In some embodiments, granulation blend consisting of CompoundA-HCl SDD, mannitol, microcrystalline cellulose, crospovidone, colloidalsilicon dioxide are prepared and blended. The intra-granular portion ofthe magnesium stearate is screened and added to the granulation blend.The resulting blend is blended. Granulation blend is charged into hopperof the roller compaction and compacted into ribbons. The ribbons arepassed through mesh screen using in-line oscillating mill to break upthe ribbons and mill into granules.

In some embodiments, the granulation blend comprises about 20% to about35% (w/w of the final tablet weight) Compound A-HCl SDD. In someembodiments, the granulation blend comprises about 21%, about 22%, about28%, 29%, about 33%, about 34% (w/w of the final tablet weight) CompoundA-HCl SDD. In some embodiments, the Compound A-HCl SDD comprises a 15/85Compound A-HCl/HPMCAS-M, 15/85 Compound A-HCl/PVPVA64, or 35/65 CompoundA-HCl/PVPVA 64 SDD.

Stage 3: Blending: The intra-granular material is mixed with theextragranular excipients. Extragranular excipients comprise one or moreexcipients selected from: fillers, disintegrants, glidants, andlubricants. The extragranular components include microcrystallinecellulose, crospovidone, colloidal silicon dioxide. The extragranularlubricant, magnesium stearate, is sieved using an appropriately sizedscreen, then added to the blend and mixed.

Stage 4: Compression: The final blend is compressed into tablets.

Stage 5: Pan-Coating: Film coating suspension of Opadry White 03K18416.is prepared in purified water, and tablets are coated with Opadry White03K18416 in a perforated coating pan.

Example 4: Evaluation of Formulation Performance in Dogs Study Designs

Evaluated two conditions* in the dog: +Pg pretreatment (mimics humanfasted stomach, pH 1-2) and −Pg pretreatment (mimics humans taking PPIsor antacids, pH 3-5). (*: 1-week washout between each condition;Pg=pentagastrin.)

Compound A-HCl Solution

N=4 non-naïve dog. Vehicle: propylene glycol. Conditions: −Pg.

Compound A-HCl HMG Capsule

N=4 non-naïve dog. Conditions: +Pg, −Pg.

Compound A-HCl Spray-Dried Dispersion Tablets: PVPVA

2 groups of N=6 non-naïve male dogs. Conditions: +Pg, −Pg.

Results from this study is presented in Tables 15 and 16.

TABLE 15 Dog PK evaluation of formulations of Compound A-HCl 20 mg 20 mgPVPVA HMG capsule SDD tablets PK Solution Fasted Fasted Fasted FastedParameters (−Pg) +Pg −Pg +Pg −Pg C_(max) (ng/mL)   191 ± 55.2 126 ± 99.614.2 ± 2.9  67.5 ± 41.3 125 ± 72.6 AUC_(0-t) 1390 ± 559 874 ± 623  85.2± 32.6 366 ± 243 454 ± 226  (ng*hr/mL)

As shown in Table 15 and FIG. 2, the HMG capsule formulations performedpoorly in dogs not pretreated with pentagastrin, whereas the spray-drieddispersions tablets performed better; For HMG capsule formulation, AUCwithout pentagastrin was only 11% of the AUC with pentagastrin (98.2ng*hr/mL compared to 917 ng*hr/mL). In comparison, the AUC for the PVPVASDD tablet formulations without pentagastrin was 185% and 124% of withpentagastrin condition, respectively. These data show that PVPVA SDDtablet formulations are superior under high gastric pH environment(e.g., as would be in subjects that are taking PPI or antacids).

TABLE 16 Dog PK evaluation of 60 mg 35/65 PVP-VA SDD tablet of CompoundA-HCl PK 35% SDD 60 mg PVPVA SDD tablet Parameters Suspension Tablet C3Tablet C4 Tablet C5 C_(max) (ng/mL) 437 ± 140 377 ± 129 329 ± 144 357 ±146 AUC_(0-t) 3630 ± 1990 3110 ± 1360 2540 ± 1120 2560 ± 1140 (ng*hr/mL)

Example 5: A Phase 1, Multi-Cohort, Single Dose Study to Assess theRelative Bioavailability, Performance, and Safety of Two Formulations ofCompound a

The study was conducted in up to 3 cohorts, each with a specific primaryobjective:

Cohort 1: To characterize performance of 10 mg tablets prepared byspray-dried dispersion (SDD) of Compound A-HCl salt.

Cohort 2: To evaluate the relative bioavailability of 10 mg SDD tabletscompared to the Compound A-HCl hot melt granulation (HMG) formulation,10 mg capsules. To determine the effect of timing of food administrationon pharmacokinetics of low dose of the 10 mg SDD tablets.

Cohort 3: To determine the effect of timing of food administration onpharmacokinetics of SDD tablets and dose proportionality in doses higherthan 20 mg. To determine the optimal dosing regimen that results inadequate systemic exposure with short post-dose fasting duration.

Study Design:

Up to thirty-six (36) healthy male and female subjects were enrolled.Cohorts 1-2 consisted of four periods each, and Cohort 3 consisted ofthree periods.

Cohort 1:

The SDD tablets were evaluated. Up to twelve (12) healthy male andfemale subjects were enrolled in each cohort. Cohort 1 consisted of 4periods: In Period 1, subjects were administered a proton-pump inhibitor(lansoprazole, 15 mg BID for 3 days (from Day −3), taken orally at least30 min prior to a meal, once in the morning and once in the evening). Onthe fourth day (Day 1 of study), fasted subjects will take the last doseof lansoprazole (15 mg) 60 min prior to 20 mg Compound A (2×10 mg of theSDD tablets). In Period 2, fasted subjects were administered 20 mgCompound A (2×10 mg of the SDD tablets). In Period 3, fasted subjectswere administered 20 mg Compound A (2×10 mg of the SDD tablets) with ahigh-fat, high-calorie meal. In Period 4, fasted subjects will take upto 80 mg Compound A (up to 8×10 mg of the SDD tablets). The actual dosewas selected based on the pharmacokinetic data from Period 2.

For Period 1: In the evening before dosing (Day −1), subjects wereadministered their evening dose of 15 mg lansoprazole, provided anevening meal at least 30 min after administration of lansoprazole, andthen were required to fast overnight (≥10 hr) on Day −1. On Day 1, theywere administered the morning dose (last dose) of 15 mg lansoprazole atleast 60 min prior to administration of Compound A (2×10 mg SDDtablets). Subjects continued to fast for 2 hr after Compound A, afterwhich they were allowed to ingest a standard meal.

For Period 2: Subjects were required to fast overnight (≥10 hr) on Day7. On Day 8, 20 mg Compound A (2×10 mg SDD tablets) was administeredorally. Subjects continued to fast for 2 hr after Compound A, afterwhich they were allowed to ingest a standard meal.

For Period 3: Subjects were required to fast overnight (≥10 hr) on Day14. On Day 15, they were allowed to ingest a high-fat, high-calorie mealwithin 30 min. Upon completion of the ingestion of the meal, Compound A(2×10 mg SDD tablets) was administered (no more than 30 min after thestart of the meal). No additional food was provided for at least 4 hrafter administration of Compound A.

Subjects were not allowed to perform strenuous exercise of >30 min/day 3days prior to Day −1 and throughout the study.

PK and safety assessments including adverse event (AE) monitoring,clinical laboratory tests, vital sign measurements, 12-lead ECGs, Holterand telemetry monitoring (Period 4 only), and physical examinations wereconducted at scheduled times throughout the study.

Cohort 2:

The cohort consisted of four periods. In each period, a single dose of20 mg Compound A (2×10 mg SDD) was administered orally.

For Period 1: Subjects were required to fast overnight (≥10 hr) on Day−1. On Day 1, a low-fat meal was given 2 hours after administration of20 mg Compound A (2×10 mg HMG capsules; reference formulation).

For Period 2: Subjects were required to fast overnight (≥10 hr) on Day7. On Day 8, they were given a low-fat meal 2 hr after administration of20 mg Compound A (2×10 mg SDD tablets; test formulation).

For Period 3: Subjects were required to fast overnight (≥10 hr) on Day14. On Day 15, they were given a low-fat meal 1 hr after administrationof 20 mg Compound A (2×10 mg SDD tablets).

For Period 4: Subjects were required to fast overnight (≥10 hr) on Day21. On Day 22, they were given a low-fat meal 0.5 hr afteradministration of 20 mg Compound A (2×10 mg SDD tablets).

The final study visit occurred on Day 29. Subjects were not allowed toperform strenuous exercise of >30 min/day, 3 days prior to Day −1 andthroughout the study. PK and safety assessments including adverse event(AE) monitoring, clinical laboratory tests, vital sign measurements,12-lead ECGs, and physical examinations were conducted at scheduledtimes throughout the study.

Cohort 3:

The cohort consisted of three periods. In each period, a single dose ofCompound A SDD (40, 60, or 80 mg) was administered orally (4×10 mg SDDtablets, 6×10 mg SDD tablets, or 8×10 mg SDD tablets). There was awashout period of at least 10 days between each dose of Compound A.

For Period 1: Subjects were required to fast overnight (≥10 hr) on Day−1. On Day 1, they were given a standard meal 1 hr after administrationof 40 mg Compound A (4×10 mg SDD tablets).

For Period 2: Subjects were required to fast overnight (≥10 hr) on Day10. On Day 11, they were given a standard meal 1 hr or 2 hr afteradministration of 80 Compound A (8×10 mg SDD tablets). The timing of themeal (1 hr or 2 hr post administration of Compound A) was dependent onthe mean AUC₀₋₂₄ determined in Period 1.

For Period 3: Subjects were required to fast overnight (≥10 hr) on Day20. On Day 21, they were given a standard meal 1 hr or 4 hr afteradministration of 60 or 80 mg Compound A (6×10 mg SDD tablets or 8×10 mgSDD tablets). The dose and timing of the standard meal was dependent onthe mean AUC₀₋₂₄ determined in Period 2.

The final study visit occurred on Day 29. Subjects were not allowed toperform strenuous exercise of >30 min/day, 3 days prior to Day −1 andthroughout the study. PK and safety assessments including adverse event(AE) monitoring, clinical laboratory tests, vital sign measurements,12-lead ECGs, and physical examinations were conducted at scheduledtimes throughout the study.

Study Population:

Up to 36 healthy male or female subjects, between the ages of 18 to 55years, inclusive, were enrolled. For Cohort 2 only, male and femalesubjects 18 to 65 years of age, inclusive, at the time of screening.

Inclusion Criteria

Each subject had to meet all of the following inclusion criteria to beenrolled in the study: Male and female subjects 18 to 55 years of age,inclusive, at the time of screening. For cohort 2 only, male and femalesubjects 18 to 65 years of age, inclusive, at the time of screening.Body mass index (BMI) of 18 to 30 kg/m², inclusive. Willing to refrainfrom strenuous, unaccustomed exercise and sports, defined as greaterthan 30 minutes per day, 3 days prior to Day −1 and throughout thestudy. If the subject was a heterosexual or bisexual female, she had tobe of non-childbearing potential OR must agree to use a highly effectiveor two clinically acceptable methods of contraception.

Exclusion Criteria

A healthy subject meeting any of the following criteria was to beexcluded from the study: Prior treatment with Compound A. Anyuncontrolled or active major systemic disease which makes studyparticipation unsafe or could interfere with evaluation of the endpointsof the study. History or presence of malignancy except adequatelytreated basal cell or squamous cell carcinomas of the skin within thepast 5 years. Active acute or chronic infection. Use of anyinvestigational drug within the past 60 days or 5 half-lives, whicheveris longer, prior to the first dosing of study drug. Use of tobaccoand/or nicotine-containing products, recreational drugs, or alcohol for48 hr prior to admission and agreement to refrain from use throughoutthe study. History of or current alcohol abuse and/or other drugaddiction <1 year prior to screening. Used any prescription orover-the-counter (OTC) medication or alternative medicinal productswithin 14 days of Day −1. Use of caffeine-containing beverages or foodfor 48 hr prior to Day −1 and for 48 hr prior to each check-in day forall subsequent periods. Have ingested foods containing poppy seedswithin 7 days before screening until completion of the studyassessments. Taking moderate or strong CYP3A4 inhibitors or inducers.Strenuous exercise for >30 min/day, 3 days prior to Day −1 andthroughout the study. Had a blood loss ≥500 mL or donated blood within 3months prior to admission. Have amylase and/or lipase levels >2×ULN,alanine aminotransferase (ALT) and/or aspartate aminotransferase(AST) >2×ULN, total bilirubin >1.5×ULN (except in the case of knownGilbert's syndrome), and/or serum creatinine above the upper limit ofnormal. History of hypersensitivity reactions to any excipients in thestudy drug. Tested positive at screening for human immunodeficiencyvirus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis Cantibody (HCV-Ab), or has a history of a positive result. Femalesubjects who have a positive serum pregnancy test or are breastfeeding.For Cohort 1 only, subjects that are classified as CYP2C19 poormetabolizers or ultra-rapid metabolizers.

Test Product, Dose, and Mode of Administration:

10 mg tablets (SDD). Multiple tablets were swallowed with waterdepending on dose specified for a given period/cohort.

Reference Therapy, Dose, and Mode of Administration:

10 mg HMG capsule formulation served as the reference formulation.Multiple capsules were swallowed with water depending on dose specifiedfor a given period/cohort.

Plasma Pharmacokinetic Parameters:

Blood PK samples were collected to evaluate Compound A plasmaconcentrations.

PK parameters were calculated for Compound A and the following are shownin tables below: Area under the plasma concentration curve from 0 to 24hours (AUC₀₋₂₄); Maximum plasma concentration (C_(max)); Time to achievemaximum plasma concentration (T_(max));

Results

Results from this clinical trial showed that the co-administration ofproton pump inhibitors only had a small effect on the pharmacokineticsobserved with the administration of the SDD tablets, shorter fastingtimes are realized with the SDD tablets and the SDD tablets providebetter dose proportional pharmacokinetics.

Results from Cohort 1 is presented in Table 17.

TABLE 17 Results from Cohort 1 Mean SD CV % Period 1 (SDD 20 mg + PPI)T_(max) (hr) 2 (1.5-3) C_(max) (ng/mL) 92.5 21.6 23.3 AUC₀₋₂₄ (hr*ng/mL)891 240 26.9 Period 2 (SDD 20 mg alone) T_(max) (hr) 3 (1.5-6) C_(max)(ng/mL) 114 40.6 35.5 AUC₀₋₂₄ (hr*ng/mL) 1140 337 29.5 Period 3 (SDD 20mg + food) T_(max) (hr) 1.8 (1.3-4)   C_(max) (ng/mL) 16.7 6.82 40.9AUC₀₋₂₄ (hr*ng/mL) 155 46.3 29.9 Period 4 (SDD 60 mg) T_(max) (hr) 3(1-6)   C_(max) (ng/mL) 305 139 45.4 AUC₀₋₂₄ (hr*ng/mL) 2900 1240 42.6P4/P2 Ratio C_(max) 3.0 (1.7-3.4) AUC₀₋₂₄ 2.8 (1.6-3.7) Median and rangeare reported for T_(max). Mean and range are reported for P4/P2 ratios.All dose administered with overnight fast and 2 h post dose fast. Food:high fat meal.

Cohort 1 (SDD 10 mg×2 under different conditions): the observedexposures with and without PPI are fairly comparable. Cohort 1 (SDD 10mg×2 vs. 10 mg×6): Relatively dose proportional increases in exposureswere observed.

In comparison to the SDD tablets, relatively dose proportional increasesin exposures were not observed with the HMG capsules. See FIG. 1. Doseproportionality data for the HMG capsules obtained from a previousclinical study is presented in Table 18.

TABLE 18 Comparative data: Dose Proportionality Observed for HMG CapsuleFormulations after single dose (4 h post dose fast). Parameter 5 mg 10mg 20 mg 30 mg 40 mg 60 mg (Mean) Day (n = 5) (n = 6) (n = 5) (n = 5) (n= 6) (n = 6) Tmax (hr) 1  1.2 ± 0.11  1.8 ± 0.94  2.4 ± 0.82  1.4 ± 0.91 3.4 ± 1.1 3.0 ± 1.2 C_(max) (ng/mL) 1 16.8 ± 7.22 78.7 ± 45.3 88.7 ±43.3 78.2 ± 60.7  185 ± 118  154 ± 77.6 AUC₀₋₂₄ 1  167 ± 73.4 661 ± 340811 ± 409 578 ± 411 1770 ± 888 1450 ± 656  (ng hr/mL) Data shown aremean ± standard deviation

Results from Cohort 2 is presented in Table 19.

TABLE 19 Results from Cohort 2 Mean SD CV % Period 1 (HMG 2 h fast)T_(max) (hr)   2 (0.75-3) C_(max) (ng/mL) 123 54.4 44.4 AUC₀₋₂₄(hr*ng/mL) 1060 462 43.6 Period 2 (SDD 2 h fast) T_(max) (hr) 2 (1-3) C_(max) (ng/mL) 97.2 32.8 33.7 AUC₀₋₂₄ (hr*ng/mL) 877 320 36.5 Period 3(SDD 1 h fast) T_(max) (hr) 1.4 (0.75-4) C_(max) (ng/mL) 89.3 37.0 41.4AUC₀₋₂₄ (hr*ng/mL) 721 319 44.2 Period 4 (SDD 30 min fast) T_(max) (hr)1.3 (0.75-4) C_(max) (ng/mL) 81.3 26.8 32.9 AUC₀₋₂₄ (hr*ng/mL) 630 21233.6 P3/P2 Ratio (%) C_(max) 92% AUC₀₋₂₄ 82% All dose administered withovernight fast.

Cohort 2 (SDD 10 mg×2 vs. HMG and under different post-dose fastingdurations): SDD tablets did not appear to have better exposures than HMGcapsules and the two formulations were relatively comparable. For theSDD tablets the AUC₀₋₂₄ (a measure of extent of absorption) after a 1 hrpost dose fast was decreased to 82% of that observed with 2 hr post-dosefast, which is a relatively small decrease in exposure.

In comparison to the performance of the SDD tablets under differentpost-dose fasting duration scenarios, the HMG capsules performed poorlyunder different post-dose fasting duration scenarios in a previouslycompleted clinical study. Pharmacokinetic data obtained afteradministering a 20 mg dose (10 mg HMG capsule×2) in 12 subjects (N=4male, N=8 Female) is presented in Table 20.

TABLE 20 Comparative Data: HMG capsule Performance Under DifferentPost-Dose Fasting Durations Post-Dose T_(max) C_(max) AUC₀₋₂₄ FastingDuration (Hr) (ng/mL) (Hr*ng/mL) 4 hour 0.75-6 134 (48.9) 1280 (344)  2hour 0.75-3 104 (35.5) 930 (293) 1 hour 0.75-3 92.2 (30.6)  654 (244)Ratio (%): — 89% 70% 2 hr/1 hr Cmax and AUC₀₋₂₄ data show are mean(standard deviation). Range is shown for Tmax.

With the HMG capsule formulations, approximately 30% loss in extent ofabsorption was noted with a 1-hour post-dose fasting vs. a 2-hourpost-dose fast.

HMG capsules with a 2 h fast was evaluated in Phase 2 clinical studies.A 1 hour fast is more desirable than a 2 hour fast. Only 18% loss ofAUC₍₀₋₂₄₎ was observed with 1 hour fast compared to a 2 hour fast. SDD 1h fast will be utilized for Phase 3. Importantly, SDD tablets appearedto have better dose proportionality than HMG capsules, allowing for 3.0×dose (i.e., 60 mg) to be administered in Phase 3 clinical studies.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

What is claimed is:
 1. A spray-dried solid dispersion comprising: (a)3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof; and (b) apharmaceutically acceptable polymer; wherein3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof, is dispersedin a polymer matrix formed from the pharmaceutically acceptable polymer.2. The spray-dried solid dispersion of claim 1, wherein: the weightratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof, to thepharmaceutically acceptable polymer is from about 1:10 to about 10:1,from about 1:1 to about 1:10, from about 1:4 to about 1:6, or from about1:1.5 to about 1:6; and the pharmaceutically acceptable polymer ishydroxypropyl methylcellulose (HPMC), hydroxypropyl methyl celluloseacetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl celluloseacetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinylacetate copolymers, polyethylene glycol, polyethylene glycolpolypropylene glycol copolymers, polyvinylpyrrolidone (PVP),polyvinylpyrrolidone polyvinyl acetate copolymers (PVP/VA), polyethylenepolyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene blockcopolymers, cellulose acetate phthalate (CAP), hydroxypropylmethyl-cellulose phthalate (HPMCP), co-polymer of methacrylic acid andmethyl methacrylate, polyethylene glycol glycerides composed of mono-,di- and triglycerides and mono- and diesters of polyethylene glycol,hydroxypropylcellulose, copolymers of ethylene oxide and propylene oxideblocks, poly(2-ethyl-2-oxazoline), poly(maleic acid/methyl vinyl ether),polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graftcopolymer, ethylene oxide/propylene oxide tetra functional blockcopolymer, d-alpha tocopheryl polyethylene glycol 1000 succinate, orcombinations thereof.
 3. The spray-dried solid dispersion of claim 2,wherein the pharmaceutically acceptable polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS), or polyvinylpyrrolidone polyvinylacetate copolymers (PVP/VA).
 4. The spray-dried solid dispersion ofclaim 2, wherein the pharmaceutically acceptable polymer ishydroxypropyl methyl cellulose acetate succinate grade M (HPMCAS-M). 5.The spray-dried solid dispersion of claim 2, wherein thepharmaceutically acceptable polymer is polyvinylpyrrolidone polyvinylacetate copolymers in a 6:4 ratio (PVP/VA 64).
 6. The spray-dried soliddispersion of claim 3, wherein the spray-dried solid dispersioncomprises at least about 5% by weight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof.
 7. Thespray-dried solid dispersion of claim 3, wherein the spray-dried soliddispersion comprises at least about 10% by weight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof.
 8. Thespray-dried solid dispersion of claim 3, wherein the spray-dried soliddispersion comprises about 15% by weight or about 35% by weight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof.
 9. Thespray-dried solid dispersion of claim 1, further comprising anon-aqueous solvent.
 10. The spray-dried solid dispersion of claim 9,wherein the non-aqueous solvent is selected from the group consisting oftert-butanol, n-propanol, n-butanol, isopropanol, ethanol, methanol,acetone, ethyl acetate, acetonitrile, methyl ethyl ketone, methylisobutyl ketone, methyl acetate, and mixtures thereof.
 11. Thespray-dried solid dispersion of claim 1, wherein3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile,or a pharmaceutically acceptable salt or solvate thereof, is3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof.
 12. A tablet comprising: thespray-dried solid dispersion of claim 1; one or more pharmaceuticalacceptable ingredients selected from the group consisting of one or morediluents, one or more disintegrants, one or more lubricants, one or moreglidants; and optionally one or more film coating agents.
 13. A tabletcomprising:3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer; one or morepharmaceutical acceptable ingredients selected from the group consistingof one or more diluents, one or more disintegrants, one or moredisintegrant aid, one or more lubricants, one or more glidants; andoptionally one or more film coating agents.
 14. The tablet of claim 13,wherein the3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer is a spray-dried soliddispersion.
 15. The tablet of claim 14, wherein the one or morepharmaceutical acceptable ingredients comprise microcrystallinecellulose, mannitol, pregelatinized starch croscarmellose sodiumcrospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride,colloidal silicon dioxide, and magnesium stearate.
 16. The tablet of 13,wherein the tablet comprises about 2% by weight to about 20% by weightof3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof.
 17. The tablet of claim 13,wherein the tablet comprises the tablet comprises about 2% by weight,about 3% by weight, about 4% by weight, about 5% by weight, about 6% byweight, about 7% by weight, about 8% by weight, about 9% by weight,about 10% by weight, about 11% by weight, about 12% by weight, about 13%by weight, about 14% by weight, or about 15% by weight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof.
 18. The tablet of claim 13,wherein the tablet comprises about 10% by weight to about 35% by weightof the polymer matrix formed from the pharmaceutically acceptablepolymer.
 19. The tablet of claim 13, wherein the tablet comprises: about2% by weight to about 15% by weight of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer, wherein the dispersed3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, in the polymer matrix is aboutabout 20% by weight to about 35% by weight of the tablet; about 40% byweight to about 80% by weight of one or more pharmaceutical acceptableingredients selected from the group consisting of one or more diluents,one or more disintegrants, one or more lubricants, one or more glidants;and optionally less than about 5% by weight of one or more film coatingagents.
 20. The tablet of claim 13, wherein the tablet comprises: about20% by weight to about 40% of a spray dried dispersion of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer; about 60% by weightto about 80% by weight of one or more pharmaceutical acceptableingredients selected from the group consisting of one or more diluents,one or more disintegrants, one or more disintegrant aids, one or morelubricants, one or more glidants; and optionally less than about 5% byweight of one or more film coating agents.
 21. The tablet of claim 20,wherein the spray dried dispersion comprises an about 15/85 to about35/65 ratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof to a polymer matrix ofhydroxypropyl methyl cellulose acetate succinate (HPMCAS), orpolyvinylpyrrolidone polyvinyl acetate copolymers (PVP/VA).
 22. Thetablet of claim 13, wherein the tablet comprises: about 20% by weight toabout 35% of by weight a spray dried dispersion of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer; wherein the spraydried dispersion comprises an about 15/85 to about 35/65 ratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof to a polymer matrix ofhydroxypropyl methyl cellulose acetate succinate (HPMCAS), orpolyvinylpyrrolidone polyvinyl acetate copolymers (PVP/VA); about 60% byweight to about 80% by weight of one or more pharmaceutical acceptableingredients selected from the group consisting of microcrystallinecellulose, mannitol, pregelatinized starch, croscarmellose sodium,crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride,silicon dioxide, and magnesium stearate; optionally less than about 5%by weight of one or more film coating agents.
 23. The tablet of claim13, wherein the tablet comprises: about 20%, about 21%, about 22%, about23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%,about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% byweight of a spray dried dispersion of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer; wherein the spraydried dispersion comprises an about 15/85 or about 35/65 ratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof to a polymer matrix ofhydroxypropyl methyl cellulose acetate succinate (HPMCAS), orpolyvinylpyrrolidone polyvinyl acetate copolymers (PVP/VA); about 60% byweight to about 80% by weight of one or more pharmaceutical acceptableingredients selected from the group consisting of one or more diluents,one or more disintegrants, one or more disintegrant aids, one or morelubricants, one or more glidants; and optionally less than about 5% byweight of one or more film coating agents.
 24. The tablet of claim 13,wherein the tablet comprises: about 20%, about 21%, about 22%, about23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%,about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% byweight of a spray dried dispersion of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, dispersed in a polymer matrixformed from a pharmaceutically acceptable polymer; wherein the spraydried dispersion comprises an about 15/85 or about 35/65 ratio of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof to a polymer matrix ofhydroxypropyl methyl cellulose acetate succinate (HPMCAS), orpolyvinylpyrrolidone polyvinyl acetate copolymers (PVP/VA); about 60% byweight to about 80% by weight of one or more pharmaceutical acceptableingredients selected from the group consisting of microcrystallinecellulose, mannitol, pregelatinized starch, croscarmellose sodium,crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride,silicon dioxide, and magnesium stearate; optionally less than about 5%by weight of one or more film coating agents.
 25. The tablet of claim13, wherein: the tablet comprises about 10 mg, about 20 mg, about 30 mg,about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof.
 26. A method of treatingacromegaly or neuroendocrine tumors, or both, in a human comprisingorally administering to the human with acromegaly or neuroendocrinetumors the tablet of claim
 13. 27. The method of claim 26, wherein: thetablet is administered once daily.
 28. The method of claim 26, wherein:the tablet is administered at least 30 minutes before a meal.
 29. Themethod of claim 26, wherein: the bioavailability of3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrilemonohydrochloride, or solvate thereof, is not substantially affected bythe coadministration of proton pump inhibitors, histamine H2-receptorantagonists, or antacids.
 30. The method of claim 26, wherein: thetablet is coadministered with a proton pump inhibitor, histamineH2-receptor antagonist, or antacid.